PRO1340 polypeptides

ABSTRACT

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

RELATED APPLICATIONS

This application is a continuation of, and claims priority under 35 USC§120 to, U.S. application Ser. No. 09/946,374 filed Sep. 4, 2001, whichis a continuation of, and claims priority under 35 USC §120 to, PCTApplication PCT/US00/04342 filed Feb. 18, 2000, which is acontinuation-in-part of, and claims priority under 35 USC §120 to, U.S.application Ser. No. 09/403,297 filed Oct. 18, 1999, now abandoned,which is the National Stage filed under 35 USC §371 of PCT ApplicationPCT/US99/20111 filed Sep. 1, 1999, which claims priority under 35 USC§119 to U.S. Provisional Application Ser. No. 60/101,916 filed Sep. 24,1998.

FIELD OF THE INVENTION

The present invention relates generally to the identification andisolation of novel DNA and to the recombinant production of novelpolypeptides.

BACKGROUND OF THE INVENTION

Extracellular proteins play important roles in, among other things, theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

Secreted proteins have various industrial applications, including aspharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents. Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci. 93: 7108-7113 (1996); U.S. Pat. No.5,536,637)].

Membrane-bound proteins and receptors can play important roles in, amongother things, the formation, differentiation and maintenance ofmulticellular organisms. The fate of many individual cells, e.g.,proliferation, migration, differentiation, or interaction with othercells, is typically governed by information received from other cellsand/or the immediate environment. This information is often transmittedby secreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides, andhormones) which are, in turn, received and interpreted by diverse cellreceptors or membrane-bound proteins. Such membrane-bound proteins andcell receptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

Membrane-bound proteins and receptor molecules have various industrialapplications, including as pharmaceutical and diagnostic agents.Receptor immunoadhesins, for instance, can be employed as therapeuticagents to block receptor-ligand interactions. The membrane-boundproteins can also be employed for screening of potential peptide orsmall molecule inhibitors of the relevant receptor/ligand interaction.

Efforts are being undertaken by both industry and academia to identifynew, native receptor or membrane-bound proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor or membrane-boundproteins.

1. PRO1560

The tetraspan family of proteins has grown to include approximately 20known genes from various species, including drosophila. The tetraspansare also known as the transmembrane 4 (TM4) superfamily and are proposedto have an organizing function in the cell membrane. Their ability tointeract with other molecules and function in such diverse activities ascell adhesion, activation and differentiation, point to a role ofaggregating large molecular complexes. Skubitz, et al., J. Immunology,157: 3617-3626 (1996). The tetraspan group has also emerged as a set ofproteins with prominent functions in Schwann cell biology. Mirsky andJessen, Curr Opin. Neurobiol., 6(1): 89-96 (1996). Tetraspans (alsosometimes called tetraspanins) are further described in Maecker, et al.,FASEB, 11: 428-442 (1997). Thus, members of the tetraspan family are ofinterest.

2. PRO444

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO444.

3. PRO1018

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1018.

4. PRO1773

The primary and rate-limiting step in retinoic acid biosynthesisrequires the conversion of retinol to retinal. Retinol dehydrogenaseproteins are enzymes which function to recognize holo-cellularretinol-binding protein as a substrate, thereby catalyzing the firststep of retinoic acid biogenesis from its substrate. Various retinoldehydrogenase genes have been cloned and characterized, wherein theproducts of these genes are suggested as potentially being useful forthe treatment of retinitis pigmentosa, psoriasis, acne and variouscancers (Chai et al., J. Biol. Chem. 270: 28408-28412 (1995) and Chai etal., Gene 169: 219-222 (1996)). Given the obvious importance of theretinol dehydrogenase enzymes, there is significant interest in theidentification and characterization of novel polypeptides havinghomology to a retinol dehydrogenase. We herein describe theidentification and characterization of novel polypeptides havinghomology to a retinol dehydrogenase protein, designated herein asPRO1773 polypeptides.

5. PRO1477

Glycosylation is an important mechanism for modulating thephysiochemical and biological properties of proteins in a stage- andtissue-specific manner. One of the important enzymes involved inglycosylation in Saccharomyces cerevisiae is alpha 1,2-mannosidase, anenzyme that catalyzes the conversion of Man9GIcNAc2 to Man8GIcNAc2during the formation of N-linked oligosaccharides. The Saccharomycescerevisiae alpha 1,2-mannosidase enzyme of is a member of the Class 1alpha 1,2-mannosidases that are conserved from yeast to mammals. Giventhe important roles played by the alpha 1,2-mannosidases and themannosidases in general in glycosylation and the physiochemical activityregulated by glycosylation, there is significant interest in identifyingnovel polypeptides having homology to one or more mannosidases. Weherein describe the identification and characterization of novelpolypeptides having homology to a mannosidase protein, designated hereinas PRO1477 polypeptides.

6. PRO1478

Recently, a new subfamily of galactosyltransferase genes that encodetype II transmembrane proteins was identified from a mouse genomiclibrary (Hennet et al., (1998) J. Biol. Chem. 273(1): 58-65).Galactosyltransferases, in general, are all of interest. Beta1,4-galactosyltransferase is been found in two subcellular compartmentswhere it is believed to perform two distinct function. Evans, et al.,Ioessays, 17(3): 261-268 (1995). Beta 1,4-galactosyltransferase isdescribed as a possible transducing receptor in Dubois and Shur, Adv.Exp. Med. Biol., 376: 105-114 (1995), and further reported on in Shur,Glycobiology, 1(6): 563-575 (1991). Expression and function of cellsurface galactosyltransferase is reported on in Shur, Biochim. Biophys.Acta., 988(3): 389-409 (1989). Moreover, the receptor function ofgalactosyltransferase during mammalian fertilization is described inShur, Adv. Exp. Biol., 207: 79-93 (1986), and the receptor functionduring cellular interactions is described in Shur, Mol. Cell Biochem.,61(2): 143-158 (1984). Thus, it is understood thatgalactosyltransferases and their related proteins are of interest.

7. PRO831

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO831.

8. PRO1113

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10): 415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2): 141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndrome,Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1): 111-116 (July1995), reporting that platelets have leucine rich repeats and Ruoslahti,E. I., et al., WO9110727-A by La Jolla Cancer Research Foundationreporting that decorin binding to transforming growth factorβ hasinvolvement in a treatment for cancer, wound healing and scarring.Related by function to this group of proteins is the insulin like growthfactor (IGF), in that it is useful in wound-healing and associatedtherapies concerned with re-growth of tissue, such as connective tissue,skin and bone; in promoting body growth in humans and animals; and instimulating other growth-related processes. The acid labile subunit ofIGF (ALS) is also of interest in that it increases the half-life of IGFand is part of the IGF complex in vivo. Another protein which has beenreported to have leucine-rich repeats is the SLIT protein which has beenreported to be useful in treating neuro-degenerative diseases such asAlzheimer's disease, nerve damage such as in Parkinson's disease, andfor diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M.,WO9210518-A1 by Yale University. Of particular interest is LIG-1, amembrane glycoprotein that is expressed specifically in glial cells inthe mouse brain, and has leucine rich repeats and immunoglobulin-likedomains. Suzuki, et al., J. Biol. Chem. (U.S.), 271(37): 22522 (1996).Other studies reporting on the biological functions of proteins havingleucine rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol.,(Ireland), 125(1-2): 65-70 (December 1996) (gonadotropin receptorinvolvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7): 1784-1789(July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc.Nephrol., 6(4): 1125-1133 (October 1995) (kidney disease involvement).

9. PRO1194

The nuclear genes PET117 and PET119 are required for the assembly ofactive cytochrome c oxidase in S. Cerevisiae, and therefore, are ofinterest. Also of interest are nucleic acids which have sequenceidentity with these genes. PET genes are further described in McEwen, etal., Curr. Genet., 23(1): 9-14 (1993).

10. PRO1110

The bone marrow plays many important roles in the mammal. One of thoseroles is to provide a source of various progenitor cells thatdifferentiate into important cells and other components of the blood andimmune systems. As such, the function of the myeloid system is ofextreme interest.

We herein describe the identification and characterization of novelpolypeptides having homology to myeloid upregulated protein, designatedherein as PRO1110 polypeptides.

11. PRO1378

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1378.

12. PRO1481

Efforts are being undertaken by both industry and academia to identifynew, native proteins. Many efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel proteins. We herein describe the identification andcharacterization of a novel protein designated herein as PRO1481.

13. PRO1189

There has been much interest in the identification of receptor proteinson stem cells and progenitor cells which may be involved in triggeringproliferation or differentiation. A type II transmembrane protein wasidentified in proliferating progenitor cells in the outer perichondrialrim of the postnatal mandibular condyle proliferation. The investigatorsconcluded that E25 could be a useful marker for chondro-osteogenicdifferentiation (Deleersnijder, et al. J. Biol. Chem. 271(32):19475-19482 (1996)).

14. PRO1415

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1415.

15. PRO1411

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1411.

16. PRO1295

Efforts arc being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1295.

17. PRO1359

Enzymes such as hyaluronidase, sialyltransferase, urokinase-typeplasminogen activator, plasmin, matrix metalloproteinases, and others,play central roles in the catabolism of extracellular matrix molecules.As such, these enzymes and inhibitors thereof, may play roles inmetastatic cancer and the treatment thereof. Van Aswegen and du Plessis,Med. Hypotheses, 48(5): 443-447 (1997). For the foregoing reason, aswell as their diversity in substrate specificity example,sialyltransferases are of particular interest. For example, a peptide ofinterest is the GalNAc alpha 2, 6-sailytransferase as described inKurosawa, et al., J. Biol. Chem., 269(2): 1402-1409 (1994). This peptidewas constructed to be secreted, and retained its catalytic activity. Theexpressed enzyme exhibited activity toward asialomucin and asialofetuin,but not other glycoproteins tested. As sialylation is an importantfunction, sialyltransferases such as this one, and peptides related bysequence identity, are of interest. Sialyltransferases are furtherdescribed in the literature, see for example, Sjoberg, et al, J. Biol.Chem., 271(13): 7450-7459 (1996), Tsuji, J. Biochem., 120(1): 1-13(1996) and Harduin-Lepers, et al., Glycobiology, 5(8): 741-758 (1995).

18. PRO1190

Kang et al. reported the identification a novel cell surfaceglycoprotein of the Ig superfamily (J. Cell biol. (1997) 138(1):203-213). Cell adhesion molecules of the Ig superfamily are implicatedin a wide variety of biological processes, including cell migration,growth control, and tumorigenesis. The Kang et al. studies suggest thatloss of CDO function may play a role in oncogenesis. Accordingly, theidentification of additional CDO-like molecules, and more generally,cell adhesion molecules of the Ig superfamily, is of interest.

19. PRO1772

Peptidases are enzymatic proteins that function to cleave peptidesubstrates either in a specific or non-specific manner. Peptidases aregenerally involved in a large number of very important biologicalprocesses in mammalian and non-mammalian organisms. Numerous differentpeptidase enzymes from a variety of different mammalian andnon-mammalian organisms have been both identified and characterized. Themammalian peptidase enzymes play important roles in many differentbiological processes including, for example, protein digestion,activation, inactivation, or modulation of peptide hormone activity, andalteration of the physical properties of proteins and enzymes.

In light of the important physiological roles played by peptidaseenzymes, efforts are currently being undertaken by both industry andacademia to identify new, native peptidase homologs. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel transmembraneproteins. Examples of screening methods and techniques are described inthe literature [see, for example, Klein et al., Proc. Natl. Acad. Sci.,93: 7108-7113 (1996); U.S. Pat. No. 5,536,637]. We herein describe theidentification of novel polypeptides having homology to variouspeptidase enzymes, designated herein as PRO1772 polypeptides.

20. PRO1248

Putative protein-2 (PUT-2) is a homolog of the human disease genesL1CAM, G6PD and P55 (Riboldi Tunnicliffe et al., Genome Analysis,submitted). As such, there is interest in identifying novel polypeptidesand encoding DNA having homology to the PUT-2 protein. We hereindescribe the identification and characterization of novel polypeptideshaving homology to PUT-2 protein, designated herein as PRO1248polypeptides.

21. PRO1316

Dickkopf (Dkk) is a family of secreted proteins having a high degree ofhomology in the cysteine-rich domains (i.e., 80-90%). Dkk-1, the firstdiscovered member, of this family has potent head-inducgin activity onthe Spemann organizer. Glinka et al., Nature 391 (6665): 357-362 (1988).The Spemann organizer of the amphibian embryo can be subdivided into twodiscrete activities, namely trunk organizer and head organizer. Dkk-1has been found to be both sufficient and necessary to cause headinduction in Xenopus embryos and is further a potent antagonist of Wntsignaling, suggesting that the Dkk genes encode an entire family of Wntinhibitors.

Members of the Wnt gene family function in both normal development anddifferentiation as well as in tumorigenesis. Wnts are encoded by a largegene family whose members have been found in round worms, insects,cartilaginous fish, and vertebrates. Holland et al., Dev. Suppl.,125-133 (1994). Wnt genes encode a family of secreted glycoproteins thatmodulate cell fate and behavior in embryos through activation ofreceptor-mediated signaling pathways.

Studies of mutations in Wnt genes have indicated a role for Wnts ingrowth control and tissue patterning. In Drosophila, wingless (wg)encodes a Wnt-related gene (Rijsewik et al., Cell, 50: 649-657 (1987))and wg mutations alter the pattern of embryonic ectoderm, neurogenesis,and imaginal disc outgrowth. Morata and Lawerence, Dev. Biol., 56:227-240 (1977); Baker, Dev. Biol., 125: 96-108 (1988); Klingensmith andNusse, Dev. Biol., 166: 396-414 (1994). In Caenorhabditis elegans,lin-44 encodes a Wnt homolog which is required for asymmetric celldivisions. Herman and Horvitz, Development, 120: 1035-1047 (1994).Knock-out mutations in mice have shown Wnts to be essential for braindevelopment (McMahon and Bradley, Cell, 62: 1073-1085 (1990); Thomas andCappechi, Nature, 346: 847-850 (1990)), and the outgrowth of embryonicprimordia for kidney (Stark et al., Nature, 372: 679-683 (1994)), tailbud (Takada et al., Genes Dev., 8: 174-189 (1994)), and limb bud. Parrand McMahon, Nature, 374: 350-353 (1995). Overexpression of Wnts in themammary gland can result in mammary hyperplasia and tumors, ((McMahon,supra (1992); Nusse and Varmus, H. E., Cell 69: 1073-1087 (1992)), andprecocious alveolar development. Bradbury et al., Dev. Biol., 170:553-563 (1995). Moreover, constitutive expression of Wnt4 in virginhosts of transplanted mammary epithelium resulted in highly branchedtissue, similar to a pregnancy-like growth pattern. Bradbury et al.,Dev. Biol. 170: 553-563 (1995).

The Wnt/Wg signal transduction pathway plays an important role in thebiological development of the organism and has been implicated inseveral human cancers. This pathway also includes the tumor suppressorgene, APC. Mutations in the APC gene are associated with the developmentof sporadic and inherited forms of human colorectal cancer. For example,elevated levels of Wnt-2 have been observed in colorectal cancers.Vider, B-Z. et al., Oncogene 12: 153-158 (1996).

22. PRO1197

Efforts are being undertaken by both industry arid academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1197.

23. PRO1293

Immunoglobulins are antibody molecules, the proteins that function bothas receptors for antigen on the B-cell membrane and as the secretedproducts of the plasma cell. Like all antibody molecules,immunoglobulins perform two major functions: they bind specifically toan antigen and they participate in a limited number of biologicaleffector functions. Therefore, new members of the Ig superfamily andfragments thereof are always of interest. Molecules which act asreceptors by various viruses and those which act to regulate immunefunction are of particular interest. Also of particular interest arethose molecules which have homology to known Ig family members which actas virus receptors or regulate immune function. Thus, molecules havinghomology to Ig superfamily members and fragments thereof (i.e., heavyand light chain fragments) are of particular interest.

We herein describe the identification and characterization of novelpolypeptides having homology to an immunoglobulin heavy chain variableregion protein, designated herein as PRO1293 polypeptides.

24. PRO1380

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1380.

25. PRO1265

The identification of novel secreted proteins involved in physiologicaland metabolic pathways is of interest because of their potential use aspharmaceutical agents. Of particular interest is the identification ofnovel polypeptides that are potentially involved in immune response andinflammation mechanisms. A novel polypeptide has recently beenidentified that is expressed in mouse B cells in response to IL-4. Thegene encoding this polypeptide is referred to as interleukin-fourinduced gene 1, or “FIG. 1” (Chu et al. Proc. Natl. Acad. Sci (1997)94(6): 2507-2512).

26. PRO1250

Long chain fatty acid CoA ligase is an enzymatic protein that functionsto ligate together long chain fatty acids, a function that playsimportant roles in a variety of different physiological processes. Giventhe importance of this enzymatic protein, efforts are currently beingundertaken to identify novel long chain fatty acid CoA ligase homologs.We herein describe the identification and characterization of novelpolypeptides having homology to long chain fatty acid CoA ligase,designated herein as PRO1250 polypeptides.

27. PRO1475

N-acetylglucosaminyltransferase proteins comprise a family of enzymesthat provide for a variety of important biological functions in themammalian organism. As an example, UDP-N-acetylglucosamine:alpha-3-D-mannoside beat-1,2-N-acetylglucosaminyltransferase I is anenzymatic protein that catalyzes an essential first step in theconversion of high-mannose N-glycans to hybrid and complex N-glycans(Sarkar et al., Proc. Natl. Acad. Sci. USA. 88: 234-238 (1991). Giventhe obvious importance of the N-acetylglucosaminyltransferase enzymes,there is significant interest in the identification and characterizationof novel polypeptides having homology to anN-acetylglucosaminyltransferase protein. We herein describe theidentification and characterization of novel polypeptides havinghomology to an N-acetylglucosaminyltransferase protein, designatedherein as PRO1475 polypeptides.

28. PRO1377

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1377.

29. PRO1326

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1326.

30. PRO1249

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1249.

31. PRO1315

Many important cytokine proteins have been identified and characterizedand shown to signal through specific cell surface receptor complexes.For example, the class II cytokine receptor family (CRF2) includes theinterferon receptors, the interleukin-10 receptor and the tissue factorCRFB4 (Spencer et al., J. Exp. Med. 187: 571-578 (1998) and Kotenko etal., EMBO J. 16: 5894-5903 (1997)). Thus, the multitude of biologicalactivities exhibited by the various cytokine proteins is absolutelydependent upon the presence of cytokine receptor proteins on the surfaceof target cells. There is, therefore, a significant interest inidentifying and characterizing novel polypeptides having homology to oneor more of the cytokine receptor family. We herein describe theidentification and characterization of a novel polypeptide havinghomology to cytokine receptor family-4 proteins, designated herein asPRO1315 polypeptides.

32. PRO1599

Granzyme M is a natural killer cell serine protease. The human gene is7.5 kilobases, has an exon-intron structure identical to other serineproteases, and is closely linked to the serine protease gene cluster onchromosome 19p13.3. (Pilat et al., Genomics, 24: 445-450 (1994)).Granzyme M has been found in two human natural killer leukemia celllines, unstimulated human peripheral blood monocytes and untreatedpurified CD3− CD56+ large granular lymphocytes. (Smyth et al., J.Immunol., 151: 6195-6205 (1993)).

33. PRO1430

Reductases form a large class of enzymatic proteins found in a varietyof mammalian tissues and play many important roles for the properfunctioning of these tissues. They are antioxidant enzymes that catalyzethe conversion of reactive oxygen species to water. Abnormal levels orfunctioning of reductases have been implicated in several diseases anddisorders including strokes, heart attacks, oxidative stress,hypertension and the development of both benign and malignant tumors.For example, malignant prostate epithelium may have lowered expressionof such antioxidant enzymes [Baker et al., Prostate 32(4): 229-233(1997)]. International patent application no. WO9622360-A1 describes aprostate specific reductase that is useful for diagnosing and treatingprostate cancer and screening new antagonists. Inhibitors ofalpha-reductase have been used in the treatment of benign prostatichyperplasia (Anderson, Drugs Aging (1996) 6(5): 388-396). For thesereasons, the identification of new members of the reductase family hasbeen of interest for the treatment and diagnosis of cancers and otherdiseases and disorders.

34. PRO1374

Prolyl 4-hyroxylase (P4HA) catalyzes the formation of 4-hydroxyprolinein collagens. Annunen, et al., J. Biol. Chem., 272(28): 17342-17348(1997); Helaakoski, et al., PNAS USA, 92(10): 4427-4431 (1995); andHopkinson, et al., Gene, 149(2): 391-392 (1994). This enzyme andmolecules related thereto are of interest.

35. PRO1311

The tetraspan family of proteins, also referred to as the “transmembrane4 (TM4) superfamily”, are proposed to have an organizing function in thecell membrane. It is believed that they interact with large molecularcomplexes and function in such diverse activities as cell adhesion,activation and differentiation (see Maecker et al. FASEB (1997) 11:428-442). Accordingly, the identification of new members of thetetraspan family of proteins is of interest. Efforts are beingundertaken by both industry and academia to identify new, nativetransmembrane proteins. Many efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel receptor proteins.

36. PRO1357

Ebnerin is a cell surface protein associated with von Ebner glands inmammals. Efforts are being undertaken by both industry and academia toidentify new, native proteins and specifically those which possesssequence homology to cell surface proteins such as ebnerin or othersalivary gland-associated proteins. Many of these efforts are focused onthe screening of mammalian recombinant DNA libraries to identify thecoding sequences for novel receptor proteins. We herein describe theidentification of novel polypeptides having significant homology to thevon Ebner minor salivary gland-associated protein, designated herein asPRO1357 polypeptides.

37. PRO1244

One type of transmembrane protein that has received attention isimplantation-associated uterine protein. Deficiencies or abnormalitiesof this protein may be a cause of miscarriage. Therefore, theidentification and characterization of implantation-associated proteinsis of interest.

38. PRO1246

Bone-related sulphatase is an enzymatic protein that has been shown todegrade sulphate groups of proteoglycan sugar chains in bone tissue(Australian Patent Publication No. AU 93/44921-A, Mar. 3, 1994). Becauseof its specific sulphatase activity, it has been suggested thatbone-related sulphatase may find use in the treatment of bone metabolicdiseases. As such, there is significant interest in identifying andcharacterizing novel polypeptides having sequence similarity tobone-related sulphatase. We herein describe the identification andcharacterization of novel polypeptides having homology to bone-relatedsulphatase, designated herein as PRO1246 polypeptides.

39. PRO1356

Clostridium perfringens enterotoxin (CPE) is considered to be thevirulence factor responsible for causing the symptoms of C. perfringenstype A food poisoning and may also be involved in other human andveterinary illnesses (McClane, Toxicon. 34: 1335-1343 (1996)). CPEcarries out its adverse cellular functions by binding to anapproximately 50 kD cell surface receptor protein designated theClostridium perfringens enterotoxin receptor (CPE-R) to form anapproximately 90,000 kD complex on the surface of the cell. cDNAsencoding the CPE-R protein have been identified characterized in bothhuman and mouse (Katahira et al., J. Cell Biol. 136: 1239-1247 (1997)and Katahira et al., J. Biol. Chem. 272: 26652-26658 (1997)). Since theCPE toxin has been reported to cause a variety of illnesses in mammalianhosts and those illnesses are initiated by binding of the CPE toxin tothe CPE-R, there is significant interest in identifying novel CPE-Rhomologs. We herein describe the identification and characterization ofnovel polypeptides having homology to the CPE-R, designated herein asPRO1356 polypeptides.

40. PRO1275

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1275.

41. PRO1274

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1274.

42. PRO1412

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1412.

43. PRO1557

The identification of secretory proteins that play roles in neuraldevelopment are of interest. Such proteins may find use in theunderstanding of and possible treatment of neurological diseases anddisorders. Chordin protein, which has been isolated from Xenopus, is apotent dorsalizing factor that regulates cell-cell interactions in theorganizing centers of Xenopus head, trunk and tail development (Sasai etal., (1994) Cell 79(5): 779-790; see also Mullins, (1998) Trends Genet.14(4): 127-129; and Kessel et al. (1998)) Trends Genet. 14(5): 169-171).It may be used as a component of culture medium for culturing nerve andmuscle cells, and may have use in the treatment of neurodegenerativediseases and neural injury (U.S. Pat. No. 5,679,783).

44. PRO1286

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1286.

45. PRO1294

The extracellular mucous matrix of olfactory neuroepithelium is a highlyorganized structure in intimate contact with chemosensory cilia thathouse the olfactory transduction machinery. The major protein componentof this extracellular matrix is olfactomedin, a glycoprotein that isexpressed in olfactory neuroepithelium and which form intermoleculardisulfide bonds so as to produce a polymer (Yokoe et al., Proc. Natl.Acad. Sci. USA 90: 4655-4659 (1993), Bal et al., Biochemistry 32:1047-1053 (1993) and Snyder et al., Biochemistry 30: 9143-9153 (1991)).It has been suggested that olfactomedin may influence the maintenance,growth or differentiation of chemosensory cilia on the apical dendritesof olfactory neurons. Given this important role, there is significantinterest in identifying and characterizing novel polypeptides havinghomology to olfactomedin. We herein describe the identification andcharacterization of a novel polypeptide having homology to olfactomedinprotein.

We herein describe the identification and characterization of novelpolypeptides having homology to olfactomedin protein, designated hereinas PRO1294 polypeptides.

46. PRO1347

Butyrophilin is a milk glycoprotein that constitutes more than 40% ofthe total protein associated with the fat globule membrane in mammalianmilk. Expression of butyrophilin mRNA has been shown to correlate withthe onset of milk fat production toward the end pregnancy and ismaintained throughout lactation. Butyrophilin has been identified inbovine, murine and human (see Taylor et al., Biochim. Biophys. Acta1306: 1-4 (1996), Ishii et al., Biochim. Biophys. Acta 1245: 285-292(1995), Mather et al., J. Dairy Sci. 76: 3832-3850 (1993), Ogg, et al.,Mamm. Genome, 7(12): 900-905 (1996), Sato, et al., J. Biochem., 117(1):147-157 (1995) and Banghart et al., J. Biol. Chem. 273: 4171-4179(1998)) and is a type I transmembrane protein that is incorporated intothe fat globulin membrane. It has been suggested that butyrophilin mayplay a role as the principle scaffold for the assembly of a complex withxanthine dehydrogenase/oxidase and other proteins that function in thebudding and release of milk-fat globules from the apical surface duringlactation (Banghart et al., supra). Given that butyrophilin plays a rolein mammalian milk production, there is substantial interest inidentifying novel butyrophilin homologs.

47. PRO1305

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1305.

48. PRO1273

The lipocalin protein family is a large group of small extracellularproteins. The family demonstrates great diversity at the sequence level;however, most lipocalins share characteristic conserved sequence motifs.Lipocalins are known to be involved in retinol transport, invertebratecryptic coloration, olfaction and pheromone transport, and prostaglandinsynthesis. The lipocalins have also been implicated in the regulation ofcell homoeostasis and the modulation of the immune response, and ascarrier proteins, to act in the general clearance of endogenous andexogenous compounds. Flower, Biochem. J., 318(Pt 1): 1-14 (1996);Flower, FEBS Lett., 354(1): 7-11 (1994). Thus, novel members of thelipocalin protein family are of interest.

49. PRO1302

CD33 is a cell-surface protein that is a member of the sialoadhesinfamily of proteins that are capable of mediating sialic-acid dependentbinding with distinct specificities for both the type of sialic acid andits linkage to subterminal sugars. CD33 is specifically expressed inearly myeloid and some monocyte cell lineages and has been shown to bestrongly associated with various myeloid tumors including, for example,acute non-lymphocytic leukemia (ANLL). As such, CD33 has been suggestedas a potential target for the treatment of cancers associated with highlevel expression of the protein. One CD33 homolog (designated CD33L) isdescribed in Takei et al. Cytogenet. Cell Genet. 78: 295-300 (1997).Another study describes the use of CD33 monoclonal antibodies in bonemarrow transplantation for acute myeloid leukemia. Robertson, et al.,Prog. Clin. Biol. Res., 389: 47-63 (1994).

Moreover, studies have reported that members of the sialoadhesion familycontribute to a range of macrophage functions, both under normalconditions as well as during inflammatory reactions. Crocker, et al.,Glycoconj. J., 14(5): 601-609 (1997). Moreover, these proteins areassociated with diverse biological processes, i.e., hemopoiesis,neuronal development and immunity. Kelm, et al., Glycoconj. J., 13(6):913-926 (1996). Thus, novel polypeptides related to CD33 by sequenceidentity are of interest.

50. PRO1283

Olfactory reception occurs via the interaction of odorants with thechemosensory cilia of the olfactory receptor cells located in the nasalepithelium. Based upon the diversity of nasal epithelial-associatedodorant binding proteins, the mammalian olfactory system is capable ofrecognizing and discriminating a large number of different odorantmolecules. In this regard, numerous different odorant binding proteinsand their encoding DNA have recently been identified and characterized(Dear et al., Biochemistry 30: 10376-10382 (1991), Pevsner et al.,Science 241: 336-339 (1988), Buck et al., Cell 65: 175-187 (1991) andBreer et al., J. Recent. Res. 13: 527-540 (1993)). Because study of themechanisms of odorant detection by the mammalian olfactory system are ofinterest, there is significant interest in identifying novel odorantbinding protein. We herein describe the identification andcharacterization of novel polypeptides having homology to odorantbinding proteins, designated herein as PRO1283 polypeptides.

51. PRO1279

Proteases are enzymatic proteins which are involved in a large number ofvery important biological processes in mammalian and non-mammalianorganisms. Numerous different protease enzymes from a variety ofdifferent mammalian and non-mammalian organisms have been bothidentified and characterized, including the serine proteases whichexhibit specific activity toward various serine-containing proteins. Themammalian protease enzymes play important roles in biological processessuch as, for example, protein digestion, activation, inactivation, ormodulation of peptide hormone activity, and alteration of the physicalproperties of proteins and enzymes.

Neuropsin is a novel serine protease whose mRNA is expressed in thecentral nervous system. Mouse neuropsin has been cloned, and studieshave shown that it is involved in the hippocampal plasticity. Neuropsinhas also been indicated as associated with extracellular matrixmodifications and cell migrations. Sce, generally, Chen, et al.,Neurosci., 7(2): 5088-5097 (1995) and Chen, et al., J. Histochem.Cytochem., 46: 313-320 (1998).

We herein describe the identification and characterization of novelpolypeptides having homology to neuropsin protein, designated herein asPRO1279 polypeptides.

52. PRO1304

The immunophilins are a family of proteins that function as receptorsfor immunosuppressant drugs, such as cyclosporin A, FK506, andrapamycin. The immunophilins occur in two separate classes, (1) theFK506-binding proteins (FKBPs), which bind to FK506 and rapamycin, and(2) the cyclophilins, which bind to cyclosporin A. With regard to theFK506-binding proteins, it has been reported that the FK506/FKBP complexfunctions to inhibit the activity of the serine/threonine proteinphosphatase 2B (calcineurin), thereby providing immunosuppressantactivity (Gold, Mol. Neurobiol. 15: 285-306 (1997)). It has also beenreported that the FKBP immunophilins are found in the mammalian nervoussystem and may be involved in axonal regeneration in the central nervoussystem through a mechanism that is independent of the process by whichimmunosuppression is achieved (Gold, supra). Thus, there is substantialinterest in identifying novel polypeptides having homology to the FKBPimmunophilins.

We herein describe the identification and characterization of novelpolypeptides having homology to FK506 binding protein, designated hereinas PRO1304 polypeptides.

53. PRO1317

There is considerable interest in the identification of molecules whoseexpression is increased upon stimulation of leukocyte populationsbecause insights into the structure and function of these molecules maylead to further understanding of the intracellular and intercellularevents that accompany activation. One such molecule, CD97, a cellsurface antigen that is rapidly upregulated upon activation onlymphocytes, has recently been the subject of several publications (seeEichler et al. in Tissue Antigens (1997) 50(50): 429-438; Aust et al.,Cancer Res. (1997) 57(9): 1798-1806). Leukocytes strongly positive forCD97 are concentrated at sites of inflammation relative to CD97expression in normal lymphoid tissue. A soluble subunit of CD97,CD97alpha, has been found in the body fluids from inflamed tissues (Grayet al. J. Immunol. (1996) 157(12): 5438-5447).

54. PRO1303

Proteases are enzymatic proteins which are involved in a large number ofvery important biological processes in mammalian and non-mammalianorganisms. Numerous different protease enzymes from a variety ofdifferent mammalian and non-mammalian organisms have been bothidentified and characterized, including the serine proteases whichexhibit specific activity toward various serine-containing proteins. Themammalian protease enzymes play important roles in biological processessuch as, for example, protein digestion, activation, inactivation, ormodulation of peptide hormone activity, and alteration of the physicalproperties of proteins and enzymes.

Neuropsin is a novel serine protease whose mRNA is expressed in thecentral nervous system. Mouse neuropsin has been cloned, and studieshave shown that it is involved in the hippocampal plasticity. Neuropsinhas also been indicated as associated with extracellular matrixmodifications and cell migrations. See, generally, Chen, et al., J.Neurosci., 7(2): 5088-5097 (1995) and Chen, et al., J. Histochem.Cytochem., 46: 313-320 (1998). Other studies have reported that kindlinginduces neuropsin mRNA in the mouse brain. Okabe, et al., Brain Res.,728(1): 116-120 (1996). Additionally, a study has reported thatgeneration of reactive oxygen species has an important role in neuropsintranscript in the limbic areas which might be related to the disturbancein avoidance learning. Akita, et al., Brain Res., 769(1): 86-96 (1997).Thus, neuropsins, and related proteins and agents, including agonistsand antagonists are of interest.

55. PRO1306

There is much interest in the identification of proteins that play rolesin mammalian disease and disorders which could lead to new methods oftreatment. A macrophage polypeptide, daintain/allograft inflammatoryfactor 1 (daintain/AIF1), has been identified in the pancreas ofprediabetic rats, and has been determined to have a direct effect oninsulin secretion. When injected intravenously in mice in low doses,daintain/AIF1 doses inhibited glucose-stimulated insulin secretion witha concomitant impairment of glucose elimination. At higher doses,daintain/AIF1 potentiated glucose-stimulated insulin secretion andenhanced glucose elimination. Thus, it was suggested that daintain/AIF1may have a role in connection with the pathogenesis of insulin-dependentdiabetes mellitus (Chen et al. Proc. Natl Acad. Sci. (1997) 94(25):13879-13884). AIF-1 has also been implicated in both rat and humanallogenic heart transplant rejection (Utans et al. Transplantation(1996) 61(9): 1387-1392), and may play a role in macrophage activationand function (Utans et al. J. Clin. Invest. (1995) 95(6): 2954-2962).

56. PRO1336

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

Leucine-rich proteins are known to be involved in protein-proteininteractions. A study has been reported on leucine-rich proteoglycanswhich serve as tissue organizers, orienting and ordering collagenfibrils during ontogeny and are involved in pathological processes suchas wound healing, tissue repair, and tumor stroma formation. Iozzo, R.V., Crit. Rev. Biochem. Mol. Biol., 32(2): 141-174 (1997). Othersstudies implicating leucine rich proteins in wound healing and tissuerepair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4): 215-222 (1995), reporting mutations in the leucine rich motif ina complex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1): 111-116 (July1995), reporting that platelets have leucine rich repeats.

Another protein of particular interest which has been reported to haveleucine-rich repeats is the slit protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. The slit protein has been characterized and reportedto be secreted by glial cells and involved in the formation of axonalpathways in Drosophila as well as the mediation of extracellular proteininteractions. Wharton and Crews, Mech. Dev., 40(3): 141-154 91993);Rothberg and Artavanis-Tsakonas, J. Mol. Biol., 227(2): 367-370 (1992);Rothberg, et al., Genes Dev., 4(12A): 2169-2187 (1990); and Rothberg, etal., Cell, 55(6): 1047-1059 (1988).

57. PRO1278

Lysozymes are secreted enzymes that preferentially hydrolyze the[beta]-1,4 glucosidic linkages between N-acetylmuramic acid andN-acetylgucosamine which occur in the mucopeptide cell wall structure ofcertain microoganisms. Lysozyme is of widespread distribution in animalsand plants. It has been found in mammalian secretions and tissuesincluding saliva, tears, milk, cervical mucus, leucocytes, kidneys, etc.The identification of new members of the lysozyme family of proteins isof interest because of the variety of roles lysozymes play in metabolicfunction and dysfunction. Abnormal levels of lysozymes have beenimplicated in various disease states. Lysozymes have been reported tohave anti-microbial, analgesic, and antinociceptive properties.Additional characteristics and possible uses of lysozymes are describedin U.S. Pat. No. 5,618,712.

58. PRO1298

Glycosylation can determine the fate of a protein, for example, whetherit is secreted or not. Also, glycoproteins play many structural andfunctional roles, particularly as part of the cell membrane. Therefore,glycosylation is of interest. Studies have reported on thegrowth-related coordinate regulation of the early N-glycosylation genesin yeast. Kukuruzinska and Lennon, Glycobiology, 4(4): 437-443 (1994).Moreover, the relationship between protein glycosylation and fattyacylation of glycoproteins was studied in the wild-type andasparagine-linked glycosylation-deficient mutants in yeast. Appukuttan,FFBS Lett., 255(1): 139-142 (1989). The biosynthesis ofasparagine-linked oligosaccharides in yeast was also studied using amutant. Jackson, et al., Glycobiology, 3(4): 357-364 (1993). Yeastmutants deficient in protein glycosylation have also been reported inHuffacker and Robbins, PNAS, 80(24): 7466-7470 (1983).

59. PRO1301

Cytochrome P450 proteins form a large class of monooxygenase enzymesinvolved in hydroxylation. Hydroxylation reactions are important in thesynthesis of cholesterol and steroid hormones. Enzymes of the cytochromeP450 family play an important role in the metabolism endogenouscompounds such as arachidonic acid. These enzymes are also important inthe metabolism of foreign substances such as the elimination of drugsfrom the body [see, for example, Peterson, Aliment. Pharmacol. Ther., 9:1-9 (1995).]. In addition, metabolites generated through the cytochromeP450 pathway may play a role in carcinogenesis, blood pressureregulation and renal function [see, for example, Rahman et al., Am. J.Hypertens., 10: 356-365 (1997)].

60. PRO1268

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1268.

61. PRO1269

Granulocytes, the most common type of white blood cell, have the abilityto mediate immunologic cytotoxicity against tumor cells andmicroorganisms. Accordingly, there has been interest in identifyingvarious factors that are produced by these cells because of theirpotential use as pharmaceutical agents. Patent publication no.WO9729765-A1, to Selsted, describes the identification of granulocytepeptide A which was isolated from bovine and murine granulocytes.Several uses for this peptide were identified including, a therapeuticuse, use as an agricultural agent, use as a preservative for food, anduse as a water treatment agent.

62. PRO1327

Neurexophilin is a protein that was discovered as a neuronalglycoprotein that was copurified with neurexin I alpha during affinitychromatography on immobilized alpha-latrotoxin (Missler et al., J.Neurosci. 18: 3630-3638 (1998)). Recent data has shown that themammalian brain contains four genes for neurexophilins the products ofwhich share a common structure composed of five domains: (1) anN-terminal signal peptide, (2) a variable N-terminal domain, (3) ahighly conserved central domain that is N-glycosylated, (4) a shortlinker region and (5) a conserved C-terminal domain that iscysteine-rich (Missler et al., supra). These data further demonstratethat the neurexophilins are proteolytically processed after synthesisand bind to alpha-neurexins. The structure and characteristics ofneurexophilins indicate that they may function as neuropeptides that maysignal via alpha-neurexins. Therefore, there is significant interest inidentifying and characterizing novel polypeptides having homology to theneurexophilins.

We herein describe the identification and characterization of novelpolypeptides having homology to neurexophilin protein, designated hereinas PRO1327 polypeptides.

63. PRO1382

Cerebellin is a secreted, postsynaptic neuroprotein found throughout thebrain. The highest concentrations of this protein have been found in thecerebellum. It has also been detected in the pituitary, spinal cord, andadrenal glands (Satoh et al. J. Endocrinol. (1997) 15491): 27-34). Thefeasibility of using cerebellum as a quantifiable marker for theinvestigation of the maturation of Purkinje cells of the cerebellum andto chart neurodevelopment has been reported (see Slemmon et al. Proc.Natl. Acad. Sci (1985) 82(20): 7145-7148). Significantly decreasedlevels of cerebellin have been found in human brains obtained inpost-mortem studies from patients with spinocerebellar degeneration,olivopontocerebellar atrophy (OPCAQ) and Shy-Drager syndrome, suggestingthat cerebellin plays important pathophysiological roles in thesecerebellar diseases (Mizuno et al. Brain Res. (1995) 686(1): 115-118;Mizuno et al. No To Shinkei (1995) 47(11): 1069-1074). In view of theimportance of cerebellin in neurodevelopment and in neurologicaldiseases and disorders, the identification and characterization ofmembers of this protein family is of interest (see also Yiangou et al.J. Neurochem (1989) 53(3): 886-889 and Mugnaini et al. Synapse (1988)2(2): 125-138).

64. PRO1328

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1328.

65. PRO1325

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1325.

66. PRO1340

Cadherins are known as the principal mediators of homotypic cellularrecognition and play a demonstrated role in the morphogenic direction oftissue development. Cadherins are a diverse family of proteins that havebeen identified in various tissues including nervous tissue (Suzuki etal. Cell Regul., 2: 261-270 (1991)). Ksp-cadherin is a kidney-specificmember of the cadherin multigene family (Thomson et al., Biol. Chem,270: 17594-17601 (1995)). Cadherins are thought to play an importantrole in human cancer (Yap, Cancer Invest., 16: 252-261 (1998)).

67. PRO1339

Carboxypeptidases are of interest. Carboxypeptidase E appears to beinvolved in the biosynthesis of a wide range of peptide hormones.Fricker, Annu. Rev. Physiol., 50: 309-321 (1988). This carboxypeptidasehas been associated with obesity. Leiter, J. Endocrinol., 155(2):211-214 (1997). Carboxypeptidase M has been reported as being a markerof macrophage maturation. Krause, et al., Immunol. Rev., 161: 119-127(1998). Human mast cell carboxypeptidase has been reported to beassociated with allergies. Goldstein, et al., Monogr. Allergy, 27:132-145 (1990). Carboxypeptidase A2 has also been reported on. Faming,et al., J. Biol. Chem., 266(36): 24606-24612 (1991). Othercarboxypeptidases of particular interest which are known in the artinclude human pancreatic carboxypeptidase 2, carboxypeptidase a1 andcarboxypeptidase B. Therefore, novel members of the carboxypeptidasefamily are of interest.

68. PRO1337

Of particular interest is the identification of blood-related proteinswhich may have potential therapeutic use or may be useful in thediagnosis of blood-related disorders. Thyroxine-binding globulin (TBG)is synthesized by the liver and secreted into the bloodstream. It is theprincipal thyroid hormone transport protein in human serum (Refetoff etal. Horm. Res. (1996) 45(3-5): 128-138). High serum levels of TBG havebeen found to cause hyperthyroxinacmia (Leahy et al., Postgrad Med. J.(1984) 60(703): 324-327). Accordingly, the identification andcharacterization of TBG proteins is of interest (see Flink et al. Proc.Natl Acad Sci. USA (1986) 83(20): 7708-7712; Bartalena et al. Acta Med.Austriaca, (1988) 15 Suppl 1: 12-15), including the identification ofabnormal TBG proteins (see Refetoff, Endocr Rev. (1989) 10(3): 275-293).Many efforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted proteins.Examples of screening methods and techniques are described in theliterature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

69. PRO1342

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1342.

70. PRO1343

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1343.

71. PRO1480

Semaphorins are a large family of transmembrane and secreted proteins,many of which are expressed in the nervous system. Members of thesemaphorin family include both ligands and receptors. (Eckhardt et al.,Mol. Cell. Neurosci., 9: 409-419 (1997)). Studies have revealed a rolefor semaphorins in embryonic motor and central nervous system axonguidance and synapse formation. (Catalano et al., Mol. Cell. Neurosci.,11: 173-182 (1998); Kitsukawa et al., Neuron, 19: 995-1005 (1997); Yu etal., Neuron, 20: 207-220 (1998)). Semaphorins have been shown to induceneuronal growth cone collapse and alter their pathway in vivo. (Shoji etal., Development, 125: 1275-1283 (1998)). Members of the semaphorinfamily have been shown to be immunologically active, inducing cytokineproduction in human monocytes. (Comeau et al., Immunity, 8: 473-482(1998)). Semaphorins may also play a role in cancer. Expression of amouse semaphorin gene is known to correlate with metastatic ability inmouse tumor cell lines. (Christensen et al., Cancer Res., 58: 1238-1244(1998)).

72. PRO1487

Fringe is a protein which specifically blocks serrate-mediatedactivation of notch in the dorsal compartment of the Drosophila wingimaginal disc (see Fleming et al., Development, 124(15): 2973-81 (1997);Wu et al. Science (1996) 273(5273): 355-358). Fringe protein is alsoinvolved in vertebrate development where a thickening of the apicalectodermal ridge essential for limb bud outgrowth involves aninteraction between dorsal cells that express radical fringe and thosethat do not (see Wolpert, L. Philos Trans R Soc Lond B Biol Sci 1998)353(1370): 871-875; Kengaku et al. Science (1998) 280(5367): 1274-1277;Cohen et al. Nat. Genet. (1997) 16(3): 283-288; Johnston et al.Development (1997) 124(11): 2245-2254; Laufer et al. Nature (1997)386(6623): 366-373; Rodriguez-Esteban et al. Nature (1997) 386(6623):360-366;).). Therefore, fringe protein is of interest for both its rolein development as well as its ability to regulate serrate, particularlyserrate's signaling abilities. Also of interest are novel polypeptideswhich may have a role in development and/or the regulation ofserrate-like molecules. Of particular interest arc novel polypeptideshaving homology to fringe protein.

73. PRO1418

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1418.

74. PRO1472

Butyrophilin is a milk glycoprotein that constitutes more than 40% ofthe total protein associated with the fat globule membrane in mammalianmilk. Expression of butyrophilin mRNA has been shown to correlate withthe onset of milk fat production toward the end pregnancy and ismaintained throughout lactation. Butyrophilin has been identified inbovine, murine and human (see Taylor et al., Biochim. Biophys. Acta1306: 1-4 (1996), Ishii et al., Biochim. Biophys. Acta 1245: 285-292(1995), Mather et al., J. Dairy Sci. 76: 3832-3850 (1993), Ogg, et al.,Mamm. Genome, 7(12): 900-905 (1996), Sato, et al., J. Biochem., 117(1):147-157 (1995) and Banghart et al., J. Biol. Chem. 273: 4171-4179(1998)) and is a type I transmembrane protein that is incorporated intothe fat globulin membrane. It has been suggested that butyrophilin mayplay a role as the principle scaffold for the assembly of a complex withxanthine dehydrogenase/oxidase and other proteins that function in thebudding and release of milk-fat globules from the apical surface duringlactation (Banghart et al., supra). Given that butyrophilin plays a rolein mammalian milk production, there is substantial interest inidentifying novel butyrophilin homologs. Members of the butyrophilinfamily are further described in Tazi-Ahnini, et al., Immunogenetics,47(1): 55-63 (1997); Davey, et al., Gene, 199(1-2): 57-62 (1997); andMather and Jack, J. Dairy Sci., 76(12): 3832-3850 (1993).

75. PRO1461

Proteases are enzymatic proteins which are involved in many biologicalprocesses in mammalian and non-mammalian organisms including digestion,protein activation and inactivation, modulation of peptide hormoneactivity, and alteration of the physical properties of proteins andenzymes. Serine proteases comprise a large class of enzymes that exhibitspecific activity toward various serine-containing proteins. Trypsin,which is synthesized by the pancreas and secreted to the smallintestine, is a well-characterized serine protease that hydrolyzespeptide bonds of ingested proteins. Trypsin-like proteases have beencharacterized that are cell-surface proteins (sec Farley et at. BiochimBiophys Acta (1993) 1173(3): 350-352; and Leytus et al. Biochemistry(1988) 27(3): 1067-1074). It is believed that some of these trypsin-likeproteins may be synthesized as a membrane-bound precursor which maturesto a soluble and active protease (Yamaoka et al. J. Biol. Chem (1998)273(19): 11895-11901).

Because of there importance in metabolism and other enzymatic processes,efforts are being undertaken by both industry and academia to identifynew, native serine-like proteases. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel receptor proteins.

76. PRO1410

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1410.

77. PRO1568

The tetraspanin (or tetraspan) family of proteins has grown to includeapproximately twenty known genes from various species. The tetraspaninsare four transmembrane domain membrane-bound molecules which include forexample, CD81, CD82, CD9, CD63, CD37 and CDS3. Many of these proteinshave a flair for promiscuous associations with other molecules,including lineage-specific proteins, integrins, and other transpanins.In terms of function, they are involved in diverse processes such ascell activation and proliferation, adhesion and motility,differentiation and cancer. One study has proposed that these functionsmay all relate to their ability to act as “molecular facilitators”,grouping specific cell-surface proteins and thus increasing theformation and stability of functional signaling complexes. Maecker, etal., FASEB, 11(6): 428-42 (1997). Another study concludes that they areresponsible for changes in cell morphology, cell-ECM adhesion andcell-signaling. Skubitz, et al., J. Immunology, 157: 3617-3626 (1996).Thus, new members of this family are of interest.

78. PRO1570

Protcases are enzymatic proteins which are involved in many biologicalprocesses in mammalian and non-mammalian organisms including digestion,protein activation and inactivation, modulation of peptide hormoneactivity, and alteration of the physical properties of proteins andenzymes. Serine proteases comprise a large class of enzymes that exhibitspecific activity toward various serine-containing proteins. Trypsin,which is synthesized by the pancreas and secreted to the smallintestine, is a well-characterized serine protease that hydrolyzespeptide bonds of ingested proteins. Trypsin-like proteases have beencharacterized that are cell-surface proteins (see Farley et al. BiochimBiophys Acta (1993) 1173(3): 350-352; and Leytus et al. Biochemistry(1988) 27(3): 1067-1074). It is believed that some of these trypsin-likeproteins may be synthesized as a membrane-bound precursor which maturesto a soluble and active protease (Yamaoka et al. J. Biol. Chem (1998)273(19): 11895-11901).

Of particular interest are human colon carcinoma derived serineproteases SP59, SP60 and SP67 which may be useful to screen for specificinhibitors or modulators to use in treatment of associated diseasestates and disorders related to these proteins. In Japanese patentJ09149790-A, SP60 is reported to be identified, having ccession numberP_W22986 and 233 amino acids.

79. PRO1317

Members of the semaphorin family of glycoproteins play important rolesin the developing nervous system, and more particularly in axonalguidance. Semaphorins have been identified in the human immune system,where they are believed to play functional roles including B-cellsignaling (Hall et al. Proc. Natl. Acad. Sci (1996) 93(21): 11780-50). Ahuman semaphorin gene, useful in the diagnosis of nervous system animmune disorders, is disclosed in Japanese Pat. No. J10155490-A,published Jun. 16, 1998. The identification of additional members of thesemaphorin family if of interest.

80. PRO1780

Enzymatic proteins that may be implicated in metabolic diseases ordisorders are of particular interest. The enzymatic addition of sugarsto fat-soluble chemicals is an important process that increases theirsolubility in water and aids in their excretion. In mammals, glucuronicacid is the main sugar that is used to prevent the waste products ofmetabolism and fat-soluble chemicals from reaching toxic levels in thebody. The UDP glucuronosyltransferases that carry out this reaction arepart of a super family of UDP glycosyltransferases found in animals,plants and bacteria. In the liver, UDP-glucuronosyltransferaseconjugates bilirubin. There are a number of conditions which affectUDP-glucuronosyltransferase activity resulting in unconjugatedhyperbilirubinemia. These conditions include genetic disorders such asCrigler-Najjar Syndrome (see Jurgen et al., Biochem. J. (1996) 314:477-483) and Gilbert syndrome, as well as acquired conditions such asLucey-Driscoll Syndrome. Accordingly, the identification of novelmembers of the glucuronosyltransferase family is of interest (see Tukeyet al., J. Biol. Chem. (1993) 268(20): 15260-6; and WO9212987-A).

81. PRO1486

The cerebellum contains a hexadecapeptide, termed cerebellin, that isconserved in sequence from human to chicken. Three independent,overlapping cDNA clones have been isolated from a human cerebellum cDNAlibrary that encode the cerebellin sequence. The longest clone codes fora protein of 193 amino acids generally termed precerebellin, or acerebellin precursor. This protein has a significant similarity to theglobular region of the B chain of human complement component C1q. Theregion of relatedness extends approximately over 145 amino acids locatedin the carboxyl terminus of both proteins. Unlike C1q B chain, nocollagen-like motifs are present in the amino-terminal regions ofprecerebellin. It is believed that cerebellin is not liberated fromprecerebellin by the classical dibasic amino acid protealytic cleavagemechanism seen in many neuropeptide precursors. The cerebellin precursorhas been associated with synaptic physiology. Urade, et al., PNAS. USA,88(3): 1069-1073 (1991). Cerebellin, its precursor, and relatedmolecules, particularly those having sequence identity with cerebellin,are therefore of interest.

82. PRO1433

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane and receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel transmembrane proteins. Weherein describe the identification and characterization of a noveltransmembrane polypeptide designated herein as PRO1433.

83. PRO1490

Enzymatic proteins play important roles in the chemical reactionsinvolved in the digestion of foods, the biosynthesis of macromolecules,the controlled release and utilization of chemical energy, and otherprocesses necessary to sustain life. Acyltransferases are enzymes whichacylate moieties. For example, acyl-glycerol-phosphate acyltransferasescan act on lysophosphatidic acid as a substrate. The lysophosphatidicacid is converted to phophatidic acid and thus plays a role in formingphosphatidylethanolamine found in membranes. See, Brown, et al., PlantMol. Biol., 26(1): 211-223 (1994). Moreover,1-acyl-sn-glyccrol-3-phosphate acyltransferase (LPAAT) is an enzymaticprotein that shows a preference for medium-chain-length fattyacyl-coenzyme A substrates. See, Knutson et al., Plant Physiol. 109:999-1006 (1995)). Thus, acyltransferases play an important role in thebiosynthesis of molecules requiring acylation.

We herein describe the identification and characterization of novelpolypeptides having homology to a 1-acyl-sn-glycerol-3-phosphateacyltransferase protein, designated herein as PRO1490 polypeptides.

84. PRO1482

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1482.

85. PRO1446

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1446.

86. PRO1558

Methyltransferase enzymes catalyze the transfer of methyl groups from adonor molecule to an acceptor molecule. Methyltransferase enzymes playextremely important roles in anumber of different biological processesincluding, for example, in the electron transport chain in the plasmamembrane in prokaryotes and in the inner mitochondrial membrane ineukaryotic cells (see, e.g., Barkovich et al., J. Biol. Chem. 272:9182-9188 (1997), Dibrov et al., J. Biol. Chem. 272: 9175-9181 (1997),Lee et al., J. Bacteriol. 179: 1748-1754 (1997) and Marbois et al.,Arch. Biochem. Biophys. 313: 83-88 (1994)). Methyltransferase enzymeshave been shown to be essential for the biosynthesis of ubiquinone(coenzyme Q) and menaquinone (vitamin K2), both of which are essentialisoprenoid quinone components of the respiratory electron transportchain. Given the obvious importance of the methyltransferase enzymes,there is substantial interest in identifying novel polypeptide homologsof the methyltransferases. We herein describe the identification andcharacterization of a novel polypeptide having homology tomethyltransferase enzymes, designated herein as PRO1558 polypeptides.

87. PRO1604

The identification of novel growth factors is of particular interestbecause of the roles they play in inducing cellular growth,proliferation and differentiation in both normal states and abnormalstates. The identification of growth factors that are over- orunder-expressed in abnormal tissues (e.g. tumors) may lead to thedevelopment of diagnostic tools and therapeutic agents. Growth factorshave been isolated from hepatoma-derived cell lines. Hepatoma-derivedgrowth factors have been isolated from mouse (Japanese Pat. No.J09313185-A, published Dec. 9, 1997) and human (Japanese Pat. No.J06343470-A, published Dec. 20, 1994) tissues. A hepatoma-derived growthfactor, isolated from a human hepatoma-derived cell line, has been foundto be ubiquitously expressed in several tumor-derived cell lines, aswell as in normal tissues (Nakamura et al., J. Biol. Chem (1994)269(40); 25143-9). The growth factor was determined to be a novelheparin-binding protein that is mitogenic for fibroblasts.

88. PRO1491

The neuronal cell body is usually round like any other cell. However,these cells have structures, also referred to as “processes”, which growfrom them to form synaptic connections. Some of these processes carryinformation away from the cell body; sometimes over very long distances.These long and thin processes are axons. The axon is a thin, statictube. Other processes carry information either towards the cell body, orboth towards and away from the cell body. These shorter and usuallythicker processes are called dendrites. Both axons and dendrites arecalled neurites.

During development and the growth stage of neurons, neurites are formedby means of growth cones. A growth cone is the growing tip of a neurite.The growth cone is flattened and highly motile. It is where new materialis added and further extension of the axon originates. Controlling wherethe growth cone crawls controls were the axon will be laid down and thuswhere it will be present.

The growth cone has several definable parts. The thin, flattened,veil-like processes that stick out and retract from the leading edge arecalled lanellipodia. The needle-like processes that stick out andretract from the leading edge are called microspikes or filopodia. Theseare the structures involved in pushing the leading edge of the growthcone forward.

The accurate navigation of growth cones to their appropriate targetsrequires that they recognize and respond to navigational cues in theirimmediate environment. Some of these cues encourage extension intocertain areas whereas others discourage extension into others. Wellcharacterized molecules that encourage neurite outgrowth in vitroinclude the extracellular matrix molecule laminin and the neuronal cellsurface molecule L1/G4/8D9. These molecules which promote neuriteextension are generally widely distributed throughout the body. Lamininimmunoreactivity is reasonably widespread in the developing central andperipheral nervous systems. Similarly, L1/G4/8D9 is present on a widevariety of neuronal processes in the developing central nervous system,particularly long projecting axons. It is, therefore, unclear whetherthe known outgrowth promoting molecules play an important role inself-specific choices growth cones make as they decide between possibleroutes. Instead, their function is believed to provide a generallypermissive environment in which growth cones extend and respond to morespecific navigational cues.

Among these more specific cues are molecules that inhibit the motilityof particular growth cones. Growth cones have been observed to losetheir motile morphology and cease advancing (collapse) on contact withother neurites of different types. Territory formation in vitro may meanthe manifestation of a process that leads to selective fasciculation invivo. Some growth cones have been observed to crawl along specificaxonal pathways, or stereotype sequences of axonal pathways indeveloping embryos. Specific motility inhibiting effects could determinewhich of several alternative pathways a growth cone will extend on.Growth cones would be expected to prefer growing on axons that do notinduce them to collapse while shunning those that do.

It has been observed that, for example, sympathetic growth cones will beinhibited or collapse when coming in contact with retinal neurites.Likewise, growth cones of retinal neurites will collapse when coming incontact with sympathetic neurites. It is believed that such cellactivity is achieved through the presence of receptors whichspecifically respond to specific growth inhibition cues by the moleculeswhich transmit specific cues pertaining to growth. Cues are believed tobe present on cell surfaces, particularly on axon surfaces.

When nerve damage occurs, repair is impeded or incapable of occurringdue to the failure of neurites to replace damaged axons or dendrites. Ifan existing neurite is damaged, severed or destroyed, a new neurite isincapable of growing out from the cell body to replace it. The presenceof molecules which inhibit neurite growth are believed to be responsiblefor the difficulty in neurite regeneration. Collapsins are proteins thatfunction to modulate the activity of molecules which modulate growthcone extension.

We herein describe the identification and characterization of novelpolypeptides having homology to a collapsin protein, designated hereinas PRO1491 polypeptides.

89. PRO1431

The transduction of intracellular signaling is crucial to cellprocessing such as differentiation, motility and division. Such signaltransduction is believed to occur throughout the cell in the form ofcomplex interactions between proteins. Such protein-protein interactionsare often mediated by modular domains within signaling proteins. As aresult, signal transduction is now modeled as a system in whichmolecules act in a combination, and the composition of that combination,determines the signal.

Src homology domains (e.g., SH2 and SH3) are two domains found inregions of sequence similarity of proteins involved in signaltransduction. Early work on the oncogenic tyrosine kinase Src identifiedthe SH2 domain. Since then, SH2 and SH3 domains have been found in manydiverse proteins, making them among the most common type of structuralmotif. SH2 and SH3 domains are modular in that they fold independentlyof the protein that contains them, their secondary structure places N-and C-termini close to one another in space, and they appear at variablelocations (anywhere from N- to C-terminal) from one protein of the next(Cohen et al., Cell 80: 237-348, 1995).

Early studies that mutated the SH2 or SH3 domain showed that these twodomains were important for function, but it was not until the cloning ofunrelated families of signaling proteins such as RAS-GAP, and the Crkoncogene that the modular nature of these domains was revealed. Theselatter experiments demonstrated that RAS-GAP and Crk bound tightly toreceptor tyrosine kinases upon ligand stimulation. Follow-up studiesdemonstrated that the mechanism of this binding was through the SH2domain and that receptor autophosphorylation was required. Such afinding implied that activation of the receptor tyrosine kinase could beviewed as a means of changing the binding aspect of the intracellulardomain, and the receptor-SH2 containing protein interaction wouldinitiate the signal transduction cascade.

SH3 domains have a more general function than that which is purportedfor SH2. SH3 binding proteins have been isolated by screeningbacteriophage expression libraries with labeled SH3 domains. The resultsof these experiments showed that SH3 domains would bind to shortproline-rich peptides, in particular the motif PxxP. Based on the levelof knowledge present at the time of the preparation of the presentpatent application, all of the SH3 binding sites identified have theproperty of being proline rich. Binding of an SH3 domain is independentof covalent modification of the binding site, such as phosphorylation asoccurs with the SH2 domain. As a result, SH3-ligand interactions areusually constitutive and not inducible, although exceptions do exist. Ingeneral, SH3 domains are less likely to act as signal “switches” than asa means of assembling protein complexes via moderate-affinityinteractions. Such moderate affinity interactions also imply that theSH3-mediated interactions will be relatively short in duration andremodeled in response to changes in concentration of binding partners.

The resolution of binding characteristics of SH2 and SH3 domains has ledto proposed compounds which would block signal transduction.Peptidomimetic ligands based on the sequence of target proteins for SH2and SH3 domains may represent new lead compounds for the therapy ofproliferative diseases that are dependent upon constitutively activatedtyrosine kinases (e.g., BCR/ABL in chronic myelogenous and acutelymphocytic leukemias or HER-2/Neu in breast and ovarian cancer).

90. PRO1563

Cellular disintegrin and metalloproteinase (ADAMs) are a family of geneswith a sequence similar to those of snake venom metalloproteinases anddisintegrins. The ADAMTS-1 gene encodes a new type of ADAM protein withrespect to possessing the thrombospondin (TSP) type I motifs, theexpression of which is associated with the inflammatory process (Kuno etal., J. Biol, Chem, 273: 13912-13917 (1998), Kuno et al., Genomics 46:466-471 (1997) and Kuno et al., J. Biol. Chem. 272: 556-562 (1997)).Expression of the ADAMTS-1 gene is induced in kidney and heart by invivo administration of lipopolysaccharide, suggesting a possible role inthe inflammation reaction. In this regard, the ADAMTS-1 protein has beensuggested as playing a possible role in various inflammatory processesas well as in the development of cancer cachexia (Kuno et al., 1998,supra). We herein describe the identification and characterization ofnovel polypeptides having homology to ADAMTS-1 protein, designatedherein as PRO1563 polypeptides.

91. PRO1565

Chondromodulin proteins are cartilage-generated matrix components thatsynergistically stimulate the growth and differentiation of chondrocytes(Suzuki, Connect. Tissue Res. 35: 303-307 (1996)). More specifically,chondromodulin-I functions to inhibit the proliferation of vascularendothelial cells and tube formation, thereby functioning to stimulatecartilage growth and inhibiting replacing cartilage by bone in an earlystage. Chondromodulin-II, while not capable of inhibitingvascularization like chondromodulin-I, also functions to stimulateosteoclast differentiation and cartilage growth. As such, these twopolypeptides are essential for the regulation of the formation ofcartilage and endochondral bone structures. Given the extremelyimportant physiological roles played by the chondromodulin proteins,there is significant interest in identifying and characterizing novelpolypeptides having homology to these proteins. We herein describe theidentification and characterization of novel polypeptides havinghomology to chondromodulin-I protein, designated herein as PRO1565polypeptides.

92. PRO1571

Clostridium perfringens enterotoxin (CPE) is considered to be thevirulence factor responsible for causing the symptoms of C. perfringenstype A food poisoning and may also be involved in other human andveterinary illnesses (McClane, Toxicon. 34: 1335-1343 (1996)). CPEcarries out its adverse cellular functions by binding to anapproximately 50 kD cell surface receptor protein designated theClostridium perfringens enterotoxin receptor (CPE-R) to form anapproximately 90,000 kD complex on the surface of the cell. cDNAsencoding the CPE-R protein have been identified characterized in bothhuman and mouse (Katahira et al., J. Cell Biol. 136: 1239-1247 (1997)and Katahira et al., J. Biol. Chem. 272: 26652-26658 (1997)). Since theCPE toxin has been reported to cause a variety of illnesses in mammalianhosts and those illnesses are initiated by binding of the CPE toxin tothe CPE-R, there is significant interest in identifying novel CPE-Rhomologs. We herein describe the identification and characterization ofnovel polypeptides having homology to the CPE-R, designated herein asPRO1679 polypeptides.

93. PRO1572

Clostridium perfringens enterotoxin utilizes two structurally relatedmembrane proteins as functional receptors in vivo. Human and mouse cDNAsshowing homology to the Clostridium enterotoxin receptor (CPE-R) genehave previously been cloned as described in Katahira, et al., J. Biol.Chem., 272(42): 26652-8 (1997). They have been classified into twogroups, the Vero cell CPE receptor homologues and rat androgenwithdrawal apoptosis protein (RVP1). These receptors are thus ofinterest as are related molecules. Of particular interest is the use ofthese receptors and related molecules in the identification ofmodulators of these receptors.

Also of interest are members of the claudin family and molecules relatedthereto. Claudins are integral membrane proteins localizing at tightjunctions with no sequence similarity to occludin. Furuse, et al., J.Cell Biol., 141(7): 1539-50 (1998).

94. PRO1573

Clostridium perfringens enterotoxin utilizes two structurally relatedmembrane proteins as functional receptors in vivo. Human and mouse cDNAsshowing homology to the Clostridium enterotoxin receptor (CPE-R) genehave previously been cloned as described in Katahira, et al., J. Biol.Chem., 272(42): 26652-8 (1997). They have been classified into twogroups, the Vero cell CPE receptor homologues and rat androgenwithdrawal apoptosis protein (RVP1). These receptors are thus ofinterest as are related molecules. Of particular interest is the use ofthese receptors and related molecules in the identification ofmodulators of these receptors.

Also of interest is the ventral prostate.1 protein (RVP.1) which istranscriptionally induced in the regressing rat prostate aftercastration. This protein is further described in Peacock, et al.,Genomics, 46(3): 443-9 (1997).

95. PRO1488

Clostridium perfringens enterotoxin utilizes two structurally relatedmembrane proteins as functional receptors in vivo. Human and mouse cDNAsshowing homology to the Clostridium enterotoxin receptor (CPE-R) genehave previously been cloned as described in Katahira, et al., J. Biol.Chem., 272(42): 26652-8 (1997), and Katahira, et al., J. Cell Biol.,136(6): 1239-1247 (1997). They have been classified into two groups, theVero cell CPE receptor homologues and rat androgen withdrawal apoptosisprotein (RVP1). These receptors are thus of interest as are relatedmolecules. Of particular interest is the use of these receptors andrelated molecules in the identification of modulators of thesereceptors.

Efforts are being undertaken by both industry and academia to identifynew, native receptor proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel receptor proteins.

96. PRO1489

Clostridium perfringens enterotoxin (CPE) is considered to be thevirulence factor responsible for causing the symptoms of C. perfringenstype A food poisoning and may also be involved in other human andveterinary illnesses (McClane, Toxicon. 34: 1335-1343 (1996)). CPEcarries out its adverse cellular functions by binding to anapproximately 50 kD cell surface receptor protein designated theClostridium perfringens enterotoxin receptor (CPE-R) to form anapproximately 90,000 kD complex on the surface of the cell. cDNAsencoding the CPE-R protein have been identified characterized in bothhuman and mouse (Katahira et al., J. Cell Biol. 136: 1239-1247 (1997)and Katahira et al., J. Biol. Chem. 272: 26652-26658 (1997)). Since theCPE toxin has been reported to cause a variety of illnesses in mammalianhosts and those illnesses are initiated by binding of the CPE toxin tothe CPE-R, there is significant interest in identifying novel CPE-Rhomologs. We herein describe the identification and characterization ofnovel polypeptides having homology to the CPE-R, designated herein asPRO1489 polypeptides.

97. PRO1474

Avian egg whites are a rich source of protein inhibitors of proteinasesbelonging to all four mechanistic classes. Ovomucoid and ovoinhibitorare multidomain Kazal-type inhibitors with each domain containing anactual or putative reactive site for a serine proteinase. Cystatin is acysteine proteinase inhibitor, while ovostatin inhibits proteinases ofall four mechanistic classes. For a review of these inhibitors, seeSaxena and Tayyab, Cell Mol. Life Sci., 53(1): 13-23 (1997). New membersof protein inhibitors of proteinases are of interest, particularly thosehaving sequence identity with known inhibitors such as ovomucoid.

Serine protease inhibitors in general are of interest. Serine proteasessuch as neuropsin have been indicated as associated with extracellularmatrix modifications and cell migrations. See, generally, Chen, et al.,Neurosci., 7(2): 5088-5097 (1995) and Chen, et al., J. Histochem.Cytochem., 46: 313-320 (1998). Another serine protease, the enamelmatrix serine proteinase, is associated with the degradation of organicmatrix in teeth. Simmer, et al., J. Dent. Res., 77(2): 377-386 (1998),Overall and Limeback, Biochem J., 256(3): 965-972 (1988), andMoradian-Oldak, Connect. Tissue Res., 35(1-4): 231-238 (1996). Thus,inhibitors of these proteases are of interest in the case that thesemechanisms require control.

98. PRO1508

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1508.

99. PRO1555

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts arc focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO1555.

100. PRO1485

Lysozymes are secreted enzymes that preferentially hydrolyze the[beta]-1,4 glucosidic linkages between N-acetylmuramic acid andN-acetylgucosamine which occur in the mucopeptide cell wall structure ofcertain microoganisms. Lysozyme is of widespread distribution in animalsand plants. It has been found in mammalian secretions and tissuesincluding saliva, tears, milk, cervical mucus, leucocytes, kidneys, etc.The identification of new members of the lysozyme family of proteins isof interest because of the variety of roles lysozymes play in metabolicfunction and dysfunction. Abnormal levels of lysozymes have beenimplicated in various disease states. Lysozymes have been reported tohave anti-microbial, analgesic, and antinueiceptive properties.Additional characteristics and possible uses of lysozymes are describedin U.S. Pat. No. 5,618,712.

Of particular interest is lysozyme C which has been recruited as adigestive enzyme in the stomachs of creatures needing to retrievenutrients from microorganisms in fermented food. The history of lysozymeC and related proteins are further described in Qasba and Kumar, Crit.Rev. Biochem. Mol. Biol., 32(4): 255-306 (1997); Irwin, EXS, 75: 347-361(1996).

101. PRO1564

Glycosylation is a common and complex form of post-translational proteinmodification. Although a large and increasing number of uniquestructures is known to exist, most arise from a series of commonsynthetic intermediates and differ at their peripheryglycosyltransferases, which recognize both the oligosaccharide acceptorand features of the underlying protein.UDP-N-acetyl-alpha-D-galactosarnine:polypeptideN-acetylgalactosaminyltransferase is an enzymatic protein that initiatesO-glycosylation of specific serine and threonine amino acids in proteinsby adding N-acetylgalactosamine to the hydroxy group of these aminoacids. Since numerous important biological and physiological events areregulted by protein glycosylation, there is significant interest inidentifying and characterizing novel polypeptides having homology to theknown glycosylation proteins. We herein describe the identification andcharacterization of novel polypeptides having homology to anN-acetylgalactosaminyltransferase protein, designated herein as PRO1564polypeptides.102. PRO1755

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO1755.

103. PRO1757

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts arc focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO1757.

104. PRO1758

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1758.

105. PRO1575

Protein Disulfide Isomerase (PDI) enhances formation of disulfide bondsin human serum albumin (HSA). Consequently, PDI assists in the formationof the overall structure of human serum albumin. Co-expression of PDIwith human serum albumin increases secretion of HSA by reducing thechance of HSA structural instability and destruction by cellularproteases. Co-expression of PDI and HSA improved localization in theendoplasmic reticulum of eukaryotic cells. (Hayano et al., EP-50941-A(1992)). PDI and the beta-subunit of human prolyl 4-hydroxylase havebeen shown to be products of the same gene. (Pihlajaniemi et al., EMBOJ., 6: 643-49 (1987)). In addition, copies of the CGHC-containing activesite sequences of PDI have been found in an abundant luminal endoplasmicreticulum protein, Erp72. (Mazzarella et al., J. Biol. Chem., 2:1094-1101 (1990)).

Efforts are being undertaken by both industry and academia to identifynew, native receptor proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel receptor proteins.

106. PRO1787

Multiple de novo MPZ (P0) point mutations have been identified in asporadic Dejerine-Sottas (DDS) case. Warner, et al., Hum. Mutat., 10(1):21-4 (1997). DDS is a severe demyelinating peripheral neuropathy withonset in infancy, and has been associated with mutations in either PMP22or MPZ. Moreover, mutational analysis of the MPZ, PMP22 and Cx32 genesin patients of Spanish ancestry with Charcot-Marie-Tooth disease andhereditary neuropathy with liability to pressure palsies have beenreported on. Bort, et al., Hum. Genet., 99(6): 746-54 (1997). Myelinglycoprotein P0 has been reported on in a number of other studies aswell (Blanquet-Grossard, et al., Clin. Genet., 48(6): 281-3 (1995),Hayasaka, et al., Nat. Genet., 5(1): 31-4 (1993) and Saavedra, et al.,J. Mol. Evol., 29(2): 149-56 (1989). Thus, proteins which may belong tothe myelin p0 family are of interest.

107. PRO1781

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO1781.

108. PRO1556

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO1556.

109. PRO1759

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO1759.

110. PRO1760

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1760.

111. PRO1561

Phospholipase A2 (PLA2) is a protein which hydrolyzes a 2-acyl esterbond of phospholipids, and examples thereof include cytosolic PLA2 andsecretory PLA2 which can be clearly distinguished from each other. Ithas been known that the cytosolic PLA2 (cPLA2) selectively hydrolyzesphospholipids containing arachidonic acid of which 2-position isesterified. Given these important biological activities, there issignificant interest in identifying and characterizing novel plypeptideshaving homology to phospholipase A2 proteins. We herein describe theidentification and characterization of novel polypeptides havinghomology to human phospholipase A2 protein, designated herein as PRO1561polypeptides.

112. PRO1567

Colon specific genes (CSGs) and their expression products are describedin published international application WO9639419. They are usefuldiagnostic markers for colon cancer and for colon cancer metastasis andcan also be used to screen for potential pharmaceutical and diagnosticagents. The identification of new members of the CSG family is ofinterest.

113. PRO1693

Insulin-like growth factors have both growth-promoting and insulin-likeactivities. There are two well characterized plasma IGF-binding proteinsin human. The larger protein is an acid-labile protein of 53K whichcirculates mostly as a 125 to 150 kD complex thought to be composed ofIGF-I or IGF-II, the binding protein itself and an acid-labilenon-IGF-binding protein with an approximate molecular mass of 100K kD.The smaller protein has an apparent molecular mass of 28K in thenon-reduced form and 34K when reduced. These IGF-binding proteins havebeen shown to play important roles in the physiological activitiesplayed by the insulin-like growth factor proteins. As such, there issubstantial interest in identifying and characterizing novelpolypeptides having homology to the insulin-like growth factor bindingproteins. We herein describe the identification and characterization ofnovel polypeptides having homology to an insulin-like growth factorbinding protein, designated herein as PRO1693 polypeptides.

114. PRO1784

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO1784.

115. PRO1605

N-acetylglucosaminyltransferase proteins comprise a family of enzymesthat provide for a variety of important biological functions in themammalian organism. As an example, UDP-N-acetylglucosamine:alpha-3-D-mannoside beat-1,2-N-acetylglucosaminyltransferase I is anenzymatic protein that catalyzes an essential first step in theconversion of high-mannose N-glycans to hybrid and complex N-glycans(Sarkar et al., Proc. Natl. Acad. Sci. USA. 88: 234-238 (1991). Giventhe obvious importance of the N-acetylglucosaminyltransferase enzymes,there is significant interest in the identification and characterizationof novel polypeptides having homology to anN-acetylglucosaminyltransferase protein. We herein describe theidentification and characterization of novel polypeptides havinghomology to an N-acetylglucosaminyltransferase protein, designatedherein as PRO1605 polypeptides.

116. PRO1788

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

Proteins containing leucine-rich repeats are thought to be involved inprotein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglobular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10): 415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2): 141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repairhave been reported including De La Salle, C., et al., Vouv. Rev. Fr.Hematol. (Germany), 37(4): 215-222 (1995), reporting mutations in theleucine rich motif in a complex associated with the bleeding disorderBernard-Soulier syndrome; Chlemetson, K. J., Thromb. Haemost. (Germany),74(1): 111-116 (July 1995), reporting that platelets have leucine richrepeats and Ruoslahti, E. I., et al.; and WO9110727-A by La Jolla CancerResearch Foundation, reporting that decorin binding to transforminggrowth factor-α has involvement in a treatment for cancer, wound healingand scarring. Related by function to this group of proteins is theinsulin like growth factor (IGF), in that it is useful in wound-healingand associated therapies concerned with re-growth of tissue, such asconnective tissue, skin and bone; in promoting body growth in humans andanimals; and in stimulating other growth-related processes. The acidlabile subunit of IGF (ALS) is also of interest in that it increases thehalf-life of IGF and is part of the IGF complex in vivo. Ollendorff, V.,et al., Cell Growth Differ, 5(2): 213-219 (February 1994) identified theGARP gene which encodes a leucine-rich repeat-containing protein thathas structural similarities with human GP Ib alpha and GP V plateletproteins, and with the Chaoptin, Toll, and Connectin adhesion moleculesof Drosophila.

Another protein which has been reported to have leucine-rich repeats isthe SLIT protein which has been reported to be useful in treatingneurodegenerative diseases such as Alzheimer's disease, nerve damagesuch as in Parkinson's disease, and for diagnosis of cancer, see,Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by YaleUniversity. Of particular interest is LIG-1, a membrane glycoproteinthat is expressed specifically in glial cells in the mouse brain, andhas leucine rich repeats and immunoglobulin-like domains. Suzuki, etal., J. Biol. Chem. (U.S.). 271(37): 22522 (1996). Other studiesreporting on the biological functions of proteins having leucine richrepeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland),125(1-2): 65-70 (December 1996) (gonadotropin receptor involvement);Miura, Y., et al., Nippon Rinsho (Japan), 54(7): 1784-1789 (July1996)(apoptosis involvement): Harris, P. C., et al., J. Am. Soc.Nephrol., 6(4): 1125-1133 (October 1995) (kidney disease involvement);and Almeida, A., et al., Oncogene 16(23): 2997-3002 (June 1998)(malignant glioma involvement).

117. PRO1801

Interleukin-10 (IL-10) is a pleiotropic immunosuppressive cytokine thathas been implicated as an important regulator of the functions ofmyeloid and lymphoid cells. It has been demonstrated that IL-10functions as a potent inhibitor of the activation of the synthesis ofvarious inflammatory cytokines including, for example, IL-1, IL-6, IFN-γand TNF-α (Gesser et al., Proc. Natl. Acad. Sci. USA 94: 14620-14625(1997)). Moreover, IL-10 has been demonstrated to strongly inhibitseveral of the accessory activities of macrophages, thereby functioningas a potent suppressor of the effector functions of macrophages, T-cellsand NK cells (Kuhn et al., Cell 75: 263-274 (1993)). Furthermore, IL-10has been strongly implicated in the regulation of B-cell, mast cell andthymocyte differentiation.

IL-10 was independently identified in two separate lines of experiments.First, cDNA clones encoding murine IL-10 were identified based upon theexpression of cytokine synthesis inhibitory factor (Moore et al.,Science 248: 1230-1234 (1990)), wherein the human IL-10 counterpartcDNAs were subsequently identified by cross-hybridization with themurine IL-10 cDNA (Viera et al., Proc. Natl. Acad. Sci. USA 88:1172-1176 (1991)). Additionally, IL-10 was independently identified as aB-cell-derived mediator which functioned to co-stimulate activethymocytes (Suda et al., Cell Immunol. 129: 228 (1990)).

Recently, a novel cytokine polypeptide which is member of theIL-10-related cytokine family has been identified and characterized.This novel secreted cytokine, designated IL-19, is a 177 amino acidpolypeptide having a molecular weight of approximately 20.4 kD (see WO98/08870, published Mar. 5, 1998). It has been reported that IL-19 isspecifically expressed by activated monocytes, wherein increased and/ordecreased levels of IL-19 may be associated with one or morephysiological disorders that arc associated with increased or decreasedlevels of cytokine production (see WO 98/08870). Specifically, IL-19 issuggested as being capable of inhibiting the synthesis of inflammatorycytokines by cells of the immune system.

Given the obvious importance of the various cytokine polypeptides and,more specifically, immunosuppressive cytokines such as IL-10 andpotentially IL-19, there is significant interest in the identificationand characterization of novel cytokine polypeptides having homology toIL-10 and/or IL-19. We herein describe the identification andcharacterization of novel polypeptides having homology to IL-19,designated herein as PRO1801 polypeptides.

118. UCP4

Uncoupling proteins or “UCPs”, believed to play a role in the metabolicprocess, have been reported in the literature. UCPs were first found anddescribed in the brown fat cells of hibernating animals, such as bears.UCPs were believed to help such hibernators and other cold-weatheradapted animals maintain core body temperatures in cold weather byraising their body's resting metabolic rate. Because humans possessrelatively small quantities of brown adipose tissue, UCPs wereoriginally thought to play a minor role in human metabolism.

Several different human uncoupling proteins have now been described.[See, generally, Gura, Science, 280: 1369-1370 (1998)]. The humanuncoupling protein referred to as UCP1 was identified by Nicholls et al.Nicholls et al. showed that the inner membrane of brown fat cellmitochondria was very permeable to proteins, and the investigatorstraced the observed permeability to a protein, called UCP1, in themitochondrial membrane. Nicholls et al. reported that the UCP1, bycreating such permeability, reduced the number of ATPs that can be madefrom a food source, thus raising body metabolic rate and generatingheat. [Nicholls et al., Physiol. Rev., 64, 1-64 (1984)].

It was later found that UCP1 is indeed expressed only in brown adiposetissue [Bouillaud et al., Proc. Natl. Acad. Sci., 82: 445-448 (1985);Jacobsson et al., J. Biol. Chem., 260: 16250-16254 (1985)]. Geneticmapping studies have shown that the human UCP1 gene is located onchromosome 4. [Cassard et al., J. Cell. Biochem., 43: 255-264 (1990)].

Another human UCP, referred to as UCPH or UCP2, has also been described.[Gimeno et al., Diabetes, 46: 900-906 (1997); Fleury et al., Nat.Genet., 15: 269-272 (1997); Boss et al., FEBS Letters, 408: 39-42(1997); see also, Wolf, Nutr. Rev., 55: 178-179 (1997)]. Fleury et al.teach that the UCP2 protein has 59% amino acid identity to UCP1, andthat UCP2 maps to regions of human chromosome 11 which have been linkedto hyperinsulinaemia and obesity. [Fleury et al., supra]. It has alsobeen reported that UCP2 is expressed in a variety of adult tissues, suchas brain and muscle and fat cells. [Gimeno et al., supra, and Fleury etal., supra].

A third human UCP, UCP3, was recently described in Boss et al., supra;Vidal-Puig et al., Biochem. Biophys. Res. Comm., 235: 79-82 (1997);Solanes et al., J. Biol. Chem., 272: 25433-25436 (1997): and Gong etal., J. Biol. Chem., 272: 24129-24132 (1997). [See also Great BritainPatent No. 9716886]. Solanes et al. report that unlike UCP1 and UCP2,UCP3 is expressed preferentially in human skeletal muscle, and that theUCP3 gene maps to human chromosome 11, adjacent to the UCP2 gene.[Solanes et al., supra]. Gong et al. describe that the UCP3 expressioncan be regulated by known thermogenic stimuli, such as thyroid hormone,beta3-andrenergic agonists and leptin. [Gong et al., supra].

119. PRO193

Efforts are being undertaken by both industry and academia to identifynew, native transmembrane proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembrane proteindesignated herein as PRO193.

120. PRO1130

Polypeptides such as the human 2-19 protein may function as cytokines.Cytokines are low molecular weight proteins which function to stimulateor inhibit the differentiation, proliferation or function of immunecells. Cytokine proteins often act as intercellular messengers and havemultiple physiological effects. Given the physiological importance ofimmune mechanisms in vivo, efforts are currently being undertaken toidentify new, native proteins which are involved in effecting the immunesystem. We describe herein the identification of a novel polypeptidewhich has sequence similarity to the human 2-19 protein.

121. PRO1335

Carbonic anhydrase is an enzymatic protein that which aids carbondioxide transport and release in the mammalian blood system bycatalyzing the synthesis (and the dehydration) of carbonic acid from(and to) carbon dioxide and water. Thus, the actions of carbonicanhydrase are essential for a variety of important physiologicalreactions in the mammal. As such, there is significant interest in theidentification and characterization of novel polypeptides havinghomology to carbonic anhydrase. We herein describe the identificationand characterization of novel polypeptides having homology to carbonicanhydrase, designated herein as PRO1335 polypeptides.

122. PRO1329

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1329.

123. PRO1550

Efforts are being undertaken by both industry and academia to identifynew, native secreted proteins. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel secreted proteins. We herein describe the identification andcharacterization of a novel secreted protein designated herein asPRO1550.

SUMMARY OF THE INVENTION

1. PRO1560

A cDNA clone (DNA 19902-1669) has been identified that encodes a novelpolypeptide believed to be a novel member of the tetraspan family,designated in the present application as “PRO1560.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1560 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95%-sequence identity to (a) a DNA moleculeencoding a PRO1560 polypeptide having the sequence of amino acidresidues from 1 or about 43 to about 245, inclusive of FIG. 2 (SEQ IDNO:4), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1560 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 167 and about775, inclusive, of FIG. 1 (SEQ ID NO:3). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No.203454(DNA 19902-1669), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203454 (DNA 19902-1669).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 or about 43 to about 245, inclusive of FIG. 2(SEQ ID NO:4), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1560polypeptide having the sequence of amino acid residues from about 1 orabout 43 to about 245, inclusive of FIG. 2 (SEQ ID NO:4), or (b) thecomplement of the DNA molecule of (a), and, if the DNA molecule has atleast about an 80% sequence identity, preferably at least about an 85%sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1560 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 42 in the sequence of FIG.2 (SEQ ID NO:4). The transmembrane domains have been tentativelyidentified as at about amino acid positions 19-42, 61-83, 92-114 and209-230 in the PRO1560 amino acid sequence (FIG. 2, SEQ ID NO:4).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 43 to about 245, inclusive of FIG. 2 (SEQ ID NO:4), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1560 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments arc from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1560polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1560 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 or about 43 through 245 of FIG. 2 (SEQ IDNO:4).

In another aspect, the invention concerns an isolated PRO1560polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 43 to about 245, inclusive of FIG. 2 (SEQ ID NO:4).

In a further aspect, the invention concerns an isolated PRO1560polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 43 through 245 of FIG. 2 (SEQ ID NO:4).

In yet another aspect, the invention concerns an isolated PRO1560polypeptide, comprising the sequence of amino acid residues 1 or about43 to about 245, inclusive of FIG. 2 (SEQ ID NO:4), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1560antibody. Preferably, the PRO1560 fragment retains a qualitativebiological activity of a native PRO1560 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1560 polypeptide having the sequence ofamino acid residues from about 1 or about 43 to about 245, inclusive ofFIG. 2 (SEQ ID NO:4), or (b) the complement of the DNA molecule of (a),and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1560 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1560 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1560 polypeptide, by contactingthe native PRO1560 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1560 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

2. PRO444

A cDNA clone (DNA26846-1393) has been identified that encodes a novelsecreted polypeptide, designated in the present application as “PRO444.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO444 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO444 polypeptide having the sequence of amino acid residuesfrom about 1 or about 17 to about 117, inclusive of FIG. 4 (SEQ IDNO:6), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO444 polypeptide comprising DNA hybridizing to thecomplement of the nucleic acid between about residues 656 and about 958,inclusive, of FIG. 3 (SEQ ID NO:5). Preferably, hybridization occursunder stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203406(DNA26846-1397), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203406 (DNA26846-1397).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 or about 17 to about 117, inclusive of FIG. 4(SEQ ID NO:6), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 10 nucleotides, more preferably at leastabout 20 nucleotides, and most preferably at least about 40 nucleotidesand produced by hybridizing a test DNA molecule under stringentconditions with (a) a DNA molecule encoding a PRO444 polypeptide havingthe sequence of amino acid residues from about 1 or about 17 to about117, inclusive of FIG. 4 (SEQ ID NO:6), or (b) the complement of the DNAmolecule of (a), and, if the DNA molecule has at least about an 80%sequence identity, preferably at least about an 85% sequence identity,more preferably at least about a 90% sequence identity, most preferablyat least about a 95% sequence identity to (a) or (b), isolating the testDNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO444 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 16 in the sequence of FIG. 4 (SEQ IDNO:6).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 17 to about 117, inclusive of FIG. 4 (SEQ ID NO:6), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO444 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO444polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO444 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 or about 17 to 117 of FIG. 4 (SEQ IDNO:6).

In another aspect, the invention concerns an isolated PRO444polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 17 to about 117, inclusive of FIG. 4 (SEQ ID NO:6).

In a further aspect, the invention concerns an isolated PRO444polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 17 to 117 of FIG. 4 (SEQ ID NO:6).

In yet another aspect, the invention concerns an isolated PRO444polypeptide, comprising the sequence of amino acid residues 1 or about17 to about 117, inclusive of FIG. 4 (SEQ ID NO:6), or a fragmentthereof sufficient to provide a binding site for an anti-PRO444antibody. Preferably, the PRO444 fragment retains a qualitativebiological activity of a native PRO444 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO444 polypeptide having the sequence ofamino acid residues from about 1 or about 17 to about 117, inclusive ofFIG. 4 (SEQ ID NO:6), or (b) the complement of the DNA molecule of (a),and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

3. PRO1018

A cDNA clone (DNA56107-1415) has been identified that encodes a noveltransmembrane polypeptide, designated in the present application as“PRO1018”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1018 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1018 polypeptide having the sequence of amino acidresidues from about 1 or about 25 to about 189, inclusive of FIG. 6 (SEQID NO:8), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1018 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 129 orabout 201 and about 695, inclusive, of FIG. 5 (SEQ ID NO:7). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203405(DNA56107-1415) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203405 (DNA56107-1415).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 25 to about 189, inclusive of FIG. 62 (SEQ IDNO:8), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1018 polypeptide having the sequence of amino acidresidues from 1 or about 25 to about 189, inclusive of FIG. 6 (SEQ IDNO:8), or (b) the complement of the DNA molecule of (a), and, if the DNAmolecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1018 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 24 in the sequence of FIG.6 (SEQ ID NO:8). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 86 to about aminoacid position 103 and from about amino acid position 60 to about aminoacid position 75 in the PRO1018 amino acid sequence (FIG. 6, SEQ IDNO:8).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 25 to about 189, inclusive of FIG. 6 (SEQ ID NO:8), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1018 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 5 (SEQ ID NO:7).

In another embodiment, the invention provides isolated PRO1018polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1018 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 25 to about 189 of FIG. 6(SEQ ID NO:8).

In another aspect, the invention concerns an isolated PRO1018polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 25 to about 189, inclusive of FIG. 6 (SEQ ID NO:8).

In a further aspect, the invention concerns an isolated PRO1018polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 25 to about 189, inclusive of FIG. 6 (SEQ ID NO:8).

In yet another aspect, the invention concerns an isolated PRO1018polypeptide, comprising the sequence of amino acid residues 1 or about25 to about 189, inclusive of FIG. 6 (SEQ ID NO:8), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1018antibody. Preferably, the PRO1018 fragment retains a qualitativebiological activity of a native PRO1018 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1018 polypeptide having the sequence ofamino acid residues from about 1 or about 25 to about 189, inclusive ofFIG. 6 (SEQ ID NO:8), or (b) the complement of the DNA molecule of (a),and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

4. PRO1773

A cDNA clone (DNA56406-1704) has been identified, having homology tonucleic acid encoding a retinol dehydrogenase protein that encodes anovel polypeptide, designated in the present application as “PRO1773”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1773 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1773 polypeptide having the sequence of amino acidresidues from about 1 or about 18 to about 319, inclusive of FIG. 8 (SEQID NO:10), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1773 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 111 orabout 162 and about 1067, inclusive, of FIG. 7 (SEQ ID NO:9).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203478(DNA56406-1704) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203478 (DNA56406-1704).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 18 to about 319, inclusive of FIG. 8 (SEQ IDNO:10), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 525 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1773 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 319, inclusive of FIG. 8 (SEQ IDNO:10), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1773 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 17 in the sequence of FIG.8 (SEQ ID NO:10). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 136 to aboutamino acid position 152 in the PRO1773 amino acid sequence (FIG. 8, SEQID NO:10).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 18 to about 319, inclusive of FIG. 8 (SEQ ID NO:10), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1773 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 7 (SEQ ID NO:9).

In another embodiment, the invention provides isolated PRO1773polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1773 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 18 to about 319 of FIG. 8(SEQ ID NO:10).

In another aspect, the invention concerns an isolated PRO1773polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 18 to about 319, inclusive of FIG. 8 (SEQ ID NO:10).

In a further aspect, the invention concerns an isolated PRO1773polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 18 to about 319, inclusive of FIG. 8 (SEQ ID NO:10).

In yet another aspect, the invention concerns an isolated PRO1773polypeptide, comprising the sequence of amino acid residues 1 or about18 to about 319, inclusive of FIG. 8 (SEQ ID NO:10), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1773antibody. Preferably, the PRO1773 fragment retains a qualitativebiological activity of a native PRO1773 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1773 polypeptide having the sequence ofamino acid residues from about 1 or about 18 to about 319, inclusive ofFIG. 8 (SEQ ID NO:10), or (b) the complement of the DNA molecule of (a),and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1773 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1773 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1773 polypeptide by contactingthe native PRO1773 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1773 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

5. PRO1477

A cDNA clone (DNA56529-1647) has been identified, having homology tonucleic acid encoding a mannosidase protein that encodes a novelpolypeptide, designated in the present application as “PRO1477”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1477 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1477 polypeptide having the sequence of amino acidresidues from about 1 to about 699, inclusive of FIG. 10 (SEQ ID NO:12),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1477 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 23 andabout 2119, inclusive, of FIG. 9 (SEQ ID NO:11). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203293(DNA56529-1647) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203293 (DNA56529-1647).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 to about 699, inclusive of FIG. 10 (SEQ ID NO:12), or(b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 540 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1477 polypeptide having the sequence of amino acidresidues from 1 to about 699, inclusive of FIG. 10 (SEQ ID NO:12), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1477 polypeptide, with or withoutand/or the initiating methionine, and its soluble, i.e., transmembranedomain deleted or inactivated variants, or is complementary to suchencoding nucleic acid molecule. The transmembrane domains have beententatively identified as extending from about amino acid position 21 toabout amino acid position 40 and from about amino acid position 84 toabout amino acid position 105 in the PRO1477 amino acid sequence (FIG.10, SEQ ID NO:12).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 699, inclusive of FIG. 10 (SEQ ID NO:12), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1477 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 9 (SEQ ID NO:11).

In another embodiment, the invention provides isolated PRO1477polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1477 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 to about 699 of FIG. 10 (SEQ IDNO:12).

In another aspect, the invention concerns an isolated PRO1477polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 699, inclusive of FIG. 10 (SEQ ID NO:12).

In a further aspect, the invention concerns an isolated PRO1477polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toabout 699, inclusive of FIG. 10 (SEQ ID NO:12).

In yet another aspect, the invention concerns an isolated PRO1477polypeptide, comprising the sequence of amino acid residues 1 to about699, inclusive of FIG. 10 (SEQ ID NO:12), or a fragment thereofsufficient to provide a binding site for an anti-PRO1477 antibody.Preferably, the PRO1477 fragment retains a qualitative biologicalactivity of a native PRO1477 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1477 polypeptide having the sequence ofamino acid residues from about 1 to about 699, inclusive of FIG. 10 (SEQID NO:12), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1477 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1477 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1477 polypeptide by contactingthe native PRO1477 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1477 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

6. PRO1478

A cDNA clone (DNA56531-1648) has been identified that encodes a novelpolypeptide having sequence identity with galactosyltransferase anddesignated in the present application as “PRO1478.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1478 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1478 polypeptide having the sequence of amino acidresidues from about 1 to about 327, inclusive of FIG. 12 (SEQ ID NO:17),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1478 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 77 and about1057, inclusive, of FIG. 11 (SEQ ID NO:16). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203286(DNA56531-1648), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203286 (DNA56531-1648).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 327, inclusive of FIG. 12 (SEQ IDNO:17), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1478polypeptide having the sequence of amino acid residues from about 1 toabout 327, inclusive of FIG. 12 (SEQ ID NO:17), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1478 polypeptide in its solubleform, i.e. transmembrane domain deleted or inactivated variants, or iscomplementary to such encoding nucleic acid molecule. The transmembranedomain (type II) has been tentatively identified as extending from aboutamino acid position 29 through about amino acid position 49 in thePRO1478 amino acid sequence (FIG. 12, SEQ ID NO:17). Therefore, apeptide including amino acids 50-327, with or without amino acids 1-28,is specifically embodied herein, as well as the nucleic acid encodingsuch a peptide.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 327, inclusive of FIG. 12 (SEQ ID NO:17), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1478 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1478polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1478 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 through 327 of FIG. 12 (SEQ ID NO:17).

In another aspect, the invention concerns an isolated PRO1478polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 327, inclusive of FIG. 12 (SEQ ID NO:17).

In a further aspect, the invention concerns an isolated PRO1478polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1through 327 of FIG. 12 (SEQ ID NO:17).

In yet another aspect, the invention concerns an isolated PRO1478polypeptide, comprising the sequence of amino acid residues 1 to about327, inclusive of FIG. 12 (SEQ ID NO:17), or a fragment thereofsufficient to provide a binding site for an anti-PRO1478 antibody.Preferably, the PRO1478 fragment retains a qualitative biologicalactivity of a native PRO1478 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1478 polypeptide having the sequence ofamino acid residues from about 1 to about 327, inclusive of FIG. 12 (SEQID NO:17), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1478 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1478 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1478 polypeptide, by contactingthe native PRO1478 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1478 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

7. PRO831

A cDNA clone (DNA56862-1343) has been identified that encodes a novelsecreted polypeptide, designated in the present application as “PRO831”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO831 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO831 polypeptide having the sequence of amino acid residuesfrom about 1 or about 16 to about 73, inclusive of FIG. 14 (SEQ IDNO:22), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO831 polypeptide comprising DNA hybridizing to thecomplement of the nucleic acid between about nucleotides 40 or about 85and about 258, inclusive, of FIG. 13 (SEQ ID NO:21). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203174(DNA56862-1343) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203174 (DNA56862-1343).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 16 to about 73, inclusive of FIG. 14 (SEQ IDNO:22), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 470 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO831 polypeptide having the sequence of amino acid residuesfrom 1 or about 16 to about 73, inclusive of FIG. 14 (SEQ ID NO:22), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO831 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 15 in the sequence of FIG. 14(SEQ ID NO:22).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 16 to about 73, inclusive of FIG. 14 (SEQ ID NO:22), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO831 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 13 (SEQ ID NO:21).

In another embodiment, the invention provides isolated PRO831polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO831 polypeptide, which in certain embodiments, includes an amino acidsequence comprising residues 1 or about 16 to about 73 of FIG. 14 (SEQID NO:22).

In another aspect, the invention concerns an isolated PRO831polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 16 to about 73, inclusive of FIG. 14 (SEQ ID NO:22).

In a further aspect, the invention concerns an isolated PRO831polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 16 to about 73, inclusive of FIG. 14 (SEQ ID NO:22).

In yet another aspect, the invention concerns an isolated PRO831polypeptide, comprising the sequence of amino acid residues 1 or about16 to about 73, inclusive of FIG. 14 (SEQ ID NO:22), or a fragmentthereof sufficient to provide a binding site for an anti-PRO831antibody. Preferably, the PRO831 fragment retains a qualitativebiological activity of a native PRO831 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO831 polypeptide having the sequence ofamino acid residues from about 1 or about 16 to about 73, inclusive ofFIG. 14 (SEQ ID NO:22), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

8. PRO1113

A cDNA clone (DNA57254-1477) has been identified that encodes a novelpolypeptide having sequence identity with leucine rich repeat proteinsand designated in the present application as “PRO1113.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1113 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1113 polypeptide having the sequence of amino acidresidues from about 1 to about 616, inclusive of FIG. 16 (SEQ ID NO:24),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1113 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 214 and about2061, inclusive, of FIG. 15 (SEQ ID NO:23). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203289(DNA57254-1477), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203289 (DNA57254-1477).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 616, inclusive of FIG. 16 (SEQ IDNO:24), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1113polypeptide having the sequence of amino acid residues from about 1 toabout 616, inclusive of FIG. 16 (SEQ ID NO:24), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1113 polypeptide in its soluble,i.e. transmembrane domain deleted or inactivated variants, or iscomplementary to such encoding nucleic acid molecule. The transmembranedomain has been tentatively identified as extending from about aminoacid position 13 through about amino acid position 40 in the PRO1113amino acid sequence (FIG. 16, SEQ ID NO:24). Thus, also presented hereinis a peptide comprising amino acids 41-616, and optionally 1-12 of SEQID NO:24, and the nucleic acids encoding the same.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 616, inclusive of FIG. 16 (SEQ ID NO:24), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1113 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1113polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1113 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 through 616 of FIG. 16 (SEQ ID NO:24).

In another aspect, the invention concerns an isolated PRO1113polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 616, inclusive of FIG. 16 (SEQ ID NO:24).

In a further aspect, the invention concerns an isolated PRO1113polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1through 616 of FIG. 16 (SEQ ID NO:24).

In yet another aspect, the invention concerns an isolated PRO1113polypeptide, comprising the sequence of amino acid residues 1 to about616, inclusive of FIG. 16 (SEQ ID NO:24), or a fragment thereofsufficient to provide a binding site for an anti-PRO1113 antibody.Preferably, the PRO1113 fragment retains a qualitative biologicalactivity of a native PRO1113 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1113 polypeptide having the sequence ofamino acid residues from about 1 to about 616, inclusive of FIG. 16 (SEQID NO:24), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1113 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1113 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1113 polypeptide, by contactingthe native PRO1113 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1113 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

9. PRO1194

A cDNA clone (DNA57841-1522) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1194.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1194 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1194 polypeptide having the sequence of amino acidresidues from 1 or about 22 to about 81, inclusive of FIG. 18 (SEQ IDNO:29), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1194 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 72 and about251, inclusive, of FIG. 17 (SEQ ID NO:28). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203458(DNA57841-1522), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203458 (DNA57841-1522).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 22 to about 81, inclusive of FIG. 18 (SEQ IDNO:29), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1194polypeptide having the sequence of amino acid residues from about 22 toabout 81, inclusive of FIG. 18 (SEQ ID NO:29), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 22to about 81, inclusive of FIG. 18 (SEQ ID NO:29), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1194 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1194polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1194 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 22 through 81 of FIG. 18 (SEQ ID NO:29).

In another aspect, the invention concerns an isolated PRO1194polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues22 to about 81, inclusive of FIG. 18 (SEQ ID NO:29).

In a further aspect, the invention concerns an isolated PRO1194polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 22through 81 of FIG. 18 (SEQ ID NO:29).

In yet another aspect, the invention concerns an isolated PRO1194polypeptide, comprising the sequence of amino acid residues 22 to about81, inclusive of FIG. 18 (SEQ ID NO:29), or a fragment thereofsufficient to provide a binding site for an anti-PRO1194 antibody.Preferably, the PRO1194 fragment retains a qualitative biologicalactivity of a native PRO1194 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1194 polypeptide having the sequence ofamino acid residues from about 22 to about 81, inclusive of FIG. 18 (SEQID NO:29), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1194 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1194 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1194 polypeptide, by contactingthe native PRO1194 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1194 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

10. PRO1110

A cDNA clone (DNA58727-1474) has been identified, having homology tonucleic acid encoding myeloid upregulated protein that encodes a novelpolypeptide, designated in the present application as “PRO1110”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1110 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1110 polypeptide having the sequence of amino acidresidues from about 1 to about 322, inclusive of FIG. 20 (SEQ ID NO:31),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1110 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 131 andabout 1096, inclusive, of FIG. 19 (SEQ ID NO:30). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203171(DNA58727-1474) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203171 (DNA58727-1474).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 to about 322, inclusive of FIG. 20 (SEQ ID NO:31), or(b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1110 polypeptide having the sequence of amino acidresidues from 1 to about 322, inclusive of FIG. 20 (SEQ ID NO:31), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1110 polypeptide, with or withoutthe initiating methionine and its soluble, i.e., transmembrane domaindeleted or inactivated variants, or is complementary to such encodingnucleic acid molecule. The transmembrane domains have been tentativelyidentified as extending from about amino acid position 41 to about aminoacid position 60, from about amino acid position 66 to about amino acidposition 85, from about amino acid position 101 to about amino acidposition 120, from about amino acid position 137 to about amino acidposition 153, from about amino acid position 171 to about amino acidposition 192, from about amino acid position 205 to about amino acidposition 226, from about amino acid position 235 to about amino acidposition 255, and from about amino acid position 294 to about amino acidposition 312 in the PRO1110 amino acid sequence (FIG. 20, SEQ ID NO:31).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 322, inclusive of FIG. 20 (SEQ ID NO:31), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1110 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments arc from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 19 (SEQ ID NO:30).

In another embodiment, the invention provides isolated PRO1110polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1110 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 to about 322 of FIG. 20 (SEQ IDNO:31).

In another aspect, the invention concerns an isolated PRO1110polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 322, inclusive of FIG. 20 (SEQ ID NO:31).

In a further aspect, the invention concerns an isolated PRO1110polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toabout 322, inclusive of FIG. 20 (SEQ ID NO:31).

In yet another aspect, the invention concerns an isolated PRO1110polypeptide, comprising the sequence of amino acid residues 1 to about322, inclusive of FIG. 20 (SEQ ID NO:31), or a fragment thereofsufficient to provide a binding site for an anti-PRO1110 antibody.Preferably, the PRO1110 fragment retains a qualitative biologicalactivity of a native PRO1110 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1110 polypeptide having the sequence ofamino acid residues from about 1 to about 322, inclusive of FIG. 20 (SEQID NO:31), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1110 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1110 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1110 polypeptide by contactingthe native PRO1110 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1110 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

11. PRO1378

A cDNA clone (DNA58730-1607) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1378”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1378 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1378 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 335, inclusive of FIG. 22 (SEQ IDNO:33), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1378 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 1365 and about2369, inclusive, of FIG. 21 (SEQ ID NO:32). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203221(DNA58730-1607), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203221 (DNA58730-1607).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from 1 or about 16 to about 335, inclusive of FIG. 22 (SEQID NO:33), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 20 nucleotides, preferably at least about50 nucleotides, and more preferably at least about 100 nucleotides andproduced by hybridizing a test DNA molecule under stringent conditionswith (a) a DNA molecule encoding a PRO1378 polypeptide having thesequence of amino acid residues from about 16 to about 335, inclusive ofFIG. 22 (SEQ ID NO:33), or (b) the complement of the DNA molecule of(a), and, if the DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), isolating the testDNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1378 polypeptide, with or withoutthe N-terminal signal sequence, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from amino acid position 1 through about aminoacid position 15 in the sequence of FIG. 22 (SEQ ID NO:33).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 16to about 335, inclusive of FIG. 22 (SEQ ID NO:33), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1378 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1378polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1378 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 16 to 335 of FIG. 22 (SEQ ID NO:33).

In another aspect, the invention concerns an isolated PRO1378polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues16 to about 335, inclusive of FIG. 22 (SEQ ID NO:33).

In a further aspect, the invention concerns an isolated PRO1378polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 16 to335 of FIG. 22 (SEQ ID NO:33).

In yet another aspect, the invention concerns an isolated PRO1378polypeptide, comprising the sequence of amino acid residues 16 to about335, inclusive of FIG. 22 (SEQ ID NO:33), or a fragment thereofsufficient to provide a binding site for an anti-PRO1378 antibody.Preferably, the PRO1378 fragment retains a qualitative biologicalactivity of a native PRO1378 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1378 polypeptide having the sequence ofamino acid residues from about 16 to about 335, inclusive of FIG. 22(SEQ ID NO:33), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

12. PRO1481

A cDNA clone (DNA58732-1650) has been identified that encodes a novelpolypeptide designated in the present application as “PRO1481.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1481 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1481 polypeptide having the sequence of amino acidresidues from 1 or about 24 to about 334, inclusive of FIG. 24 (SEQ IDNO:41), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1481 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 88 and about1321, inclusive, of FIG. 23 (SEQ ID NO:40). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203290(DNA58732-1650), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203290 (DNA58732-1650).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 24 to about 334, inclusive of FIG. 24 (SEQ IDNO:41), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1481polypeptide having the sequence of amino acid residues from about 24 toabout 334, inclusive of FIG. 24 (SEQ ID NO:41), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1481 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted, truncated or inactivatedvariants, or is complementary to such encoding nucleic acid molecule.The signal peptide has been tentatively identified as extending fromamino acid position 1 through about amino acid position 23 in thesequence of FIG. 24 (SEQ ID NO:41). Thc transmembrane domain has beententatively identified as extending from about amino acid position 235through about amino acid position 262 in the PRO1481 amino acid sequence(FIG. 24, SEQ ID NO:41).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 24to about 334, inclusive of FIG. 24 (SEQ ID NO:41), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1481 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1481polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1481 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 24 through 334 of FIG. 24 (SEQ ID NO:41).

In another aspect, the invention concerns an isolated PRO1481polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues24 to about 334, inclusive of FIG. 24 (SEQ ID NO:41).

In a further aspect, the invention concerns an isolated PRO1481polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 24through 334 of FIG. 24 (SEQ ID NO:41).

In yet another aspect, the invention concerns an isolated PRO1481polypeptide, comprising the sequence of amino acid residues 24 to about334, inclusive of FIG. 24 (SEQ ID NO:41), or a fragment thereofsufficient to provide a binding site for an anti-PRO1481 antibody.Preferably, the PRO1481 fragment retains a qualitative biologicalactivity of a native PRO1481 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1481 polypeptide having the sequence ofamino acid residues from about 24 to about 334, inclusive of FIG. 24(SEQ ID NO:41), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1481 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1481 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1481 polypeptide, by contactingthe native PRO1481 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1481 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

13. PRO1189

A cDNA clone (DNA58828-1519) has been identified that encodes a novelpolypeptide having homology to E25 which is designated in the presentapplication as “PRO1189.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1189 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1189 polypeptide having the sequence of amino acidresidues from about 1 to about 263, inclusive of FIG. 26 (SEQ ID NO:43),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1189 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 79 and about867, inclusive, of FIG. 25 (SEQ ID NO:42). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203172(DNA58828-1519), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203172 (DNA58828-1519).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 263, inclusive of FIG. 26 (SEQ IDNO:43), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO189polypeptide having the sequence of amino acid residues from about 1 toabout 263, inclusive of FIG. 26 (SEQ ID NO:43), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1189 polypeptide with itstransmembrane domain deleted or inactivated, or is complementary to suchencoding nucleic acid molecule. The transmembrane domain has beententatively identified as extending from about amino acid position 53through about amino acid position 75 in the PRO1189 amino acid sequence(FIG. 26, SEQ ID NO:43).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 263, inclusive of FIG. 26 (SEQ ID NO:43), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1189 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1189polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1189 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 263 of FIG. 26 (SEQ ID NO:43).

In another aspect, the invention concerns an isolated PRO1189polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 263, inclusive of FIG. 26 (SEQ ID NO:43).

In a further aspect, the invention concerns an isolated PRO1189polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to263 of FIG. 26 (SEQ ID NO:43).

In yet another aspect, the invention concerns an isolated PRO1189polypeptide, comprising the sequence of amino acid residues 1 to about263, inclusive of FIG. 26 (SEQ ID NO:43), or a fragment thereofsufficient to provide a binding site for an anti-PRO1189 antibody.Preferably, the PRO1189 fragment retains a qualitative biologicalactivity of a native PRO1189 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1189 polypeptide having the sequence ofamino acid residues from about 1 to about 263, inclusive of FIG. 26 (SEQID NO:43), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1189 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1189 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1189 polypeptide, by contactingthe native PRO1189 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1189 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

14. PRO1415

A cDNA clone (DNA58852-1637) has been identified that encodes a novelpolypeptide, designated in the present application as “PRO1415”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1415 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1415 polypeptide having the sequence of amino acidresidues from about 1 or about 26 to about 283, inclusive of FIG. 28(SEQ ID NO:50), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1415 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 148 orabout 223 and about 996, inclusive, of FIG. 27 (SEQ ID NO:49).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203271(DNA58852-1637) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203271 (DNA58852-1637).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 26 to about 283, inclusive of FIG. 28 (SEQ IDNO:50), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1415 polypeptide having the sequence of amino acidresidues from 1 or about 26 to about 283, inclusive of FIG. 28 (SEQ IDNO:50), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1415 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 25 in the sequence of FIG.28 (SEQ ID NO:50). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 94 to about aminoacid position 118 in the PRO1415 amino acid sequence (FIG. 28, SEQ IDNO:50).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 26 to about 283, inclusive of FIG. 28 (SEQ ID NO:50), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1415 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 27 (SEQ ID NO:49).

In another embodiment, the invention provides isolated PRO1415polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1415 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 26 to about 283 of FIG. 28(SEQ ID NO:50).

In another aspect, the invention concerns an isolated PRO1415polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 26 to about 283, inclusive of FIG. 28 (SEQ ID NO:50).

In a further aspect, the invention concerns an isolated PRO1415polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 26 to about 283, inclusive of FIG. 28 (SEQ ID NO:50).

In yet another aspect, the invention concerns an isolated PRO1415polypeptide, comprising the sequence of amino acid residues 1 or about26 to about 283, inclusive of FIG. 28 (SEQ ID NO:50), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1415antibody. Preferably, the PRO1415 fragment retains a qualitativebiological activity of a native PRO1415 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1415 polypeptide having the sequence ofamino acid residues from about 1 or about 26 to about 283, inclusive ofFIG. 28 (SEQ ID NO:50), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1415 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1415 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1415 polypeptide by contactingthe native PRO1415 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1415 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

15. PRO1411

A cDNA clone (DNA59212-1627) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1411.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1411 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1411 polypeptide having the sequence of amino acidresidues from 1 or about 22 to about 440, inclusive of FIG. 30 (SEQ IDNO:52), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1411 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 247 and about1503, inclusive, of FIG. 29 (SEQ ID NO:51). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203245(DNA59212-1627), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203245 (DNA59212-1627).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 22 to about 440, inclusive of FIG. 30 (SEQ IDNO:52), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1411polypeptide having the sequence of amino acid residues from about 22 toabout 440, inclusive of FIG. 30 (SEQ ID NO:52), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 22to about 440, inclusive of FIG. 30 (SEQ ID NO:52), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1411 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1411polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1411 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 22 through 440 of FIG. 30 (SEQ ID NO:52).

In another aspect, the invention concerns an isolated PRO1411polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues22 to about 440, inclusive of FIG. 30 (SEQ ID NO:52).

In a further aspect, the invention concerns an isolated PRO1411polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 22through 440 of FIG. 30 (SEQ ID NO:52).

In yet another aspect, the invention concerns an isolated PRO1411polypeptide, comprising the sequence of amino acid residues 22 to about440, inclusive of FIG. 30 (SEQ ID NO:52), or a fragment thereofsufficient to provide a binding site for an anti-PRO1411 antibody.Preferably, the PRO1411 fragment retains a qualitative biologicalactivity of a native PRO1411 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1411 polypeptide having the sequence ofamino acid residues from about 22 to about 440, inclusive of FIG. 30(SEQ ID NO:52), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1411 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1411 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1411 polypeptide, by contactingthe native PRO1411 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1411 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

16. PRO1295

A cDNA clone (DNA59218-1559) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1295.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1295 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1295 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 280, inclusive of FIG. 32 (SEQ IDNO:54), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1295 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 261 and about1046, inclusive, of FIG. 31 (SEQ ID NO:53). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203287(DNA59218-1559), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203287 (DNA59218-1559).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 280, inclusive of FIG. 32 (SEQ IDNO:54), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1295polypeptide having the sequence of amino acid residues from about 19 toabout 280, inclusive of FIG. 32 (SEQ ID NO:54), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 280, inclusive of FIG. 32 (SEQ ID NO: 54), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1295 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1295polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1295 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 through 280 of FIG. 32 (SEQ ID NO:54).

In another aspect, the invention concerns an isolated PRO1295polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 280, inclusive of FIG. 32 (SEQ ID NO:54).

In a further aspect, the invention concerns an isolated PRO1295polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19through 280 of FIG. 32 (SEQ ID NO:54).

In yet another aspect, the invention concerns an isolated PRO1295polypeptide, comprising the sequence of amino acid residues 19 to about280, inclusive of FIG. 32 (SEQ ID NO:54), or a fragment thereofsufficient to provide a binding site for an anti-PRO1295 antibody.Preferably, the PRO1295 fragment retains a qualitative biologicalactivity of a native PRO1295 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1295 polypeptide having the sequence ofamino acid residues from about 19 to about 280, inclusive of FIG. 32(SEQ ID NO:54), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1295 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1295 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1295 polypeptide, by contactingthe native PRO1295 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1295 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

17. PRO1359

A cDNA clone (DNA59219-1613) has been identified that encodes a novelpolypeptide having sequence identity with sialytransferases anddesignated in the present application as “PRO1359” polypeptides.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1359 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1359 polypeptide having the sequence of amino acidresidues from 1 or about 32 to about 299, inclusive of FIG. 34 (SEQ IDNO:56), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1359 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 277 and about1080, inclusive, of FIG. 33 (SEQ ID NO:55). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203220(DNA59219-1613), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203220 (DNA59219-1613).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 32 to about 299, inclusive of FIG. 34 (SEQ IDNO:56), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1359polypeptide having the sequence of amino acid residues from about 32 toabout 299, inclusive of FIG. 34 (SEQ ID NO:56), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1359 polypeptide in its soluble,i.e. transmembrane domain deleted or inactivated variants, or iscomplementary to such encoding nucleic acid molecule. The transmembranedomain (type II) has been tentatively identified as extending from aboutamino acid position 9 through about amino acid position 31 in thePRO1359 amino acid sequence (FIG. 34, SEQ ID NO:56).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 32to about 299, inclusive of FIG. 34 (SEQ ID NO:56), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1359 polypeptideceding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1359polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1359 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 32 through 299 of FIG. 34 (SEQ ID NO:56).

In another aspect, the invention concerns an isolated PRO1359polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues32 to about 299, inclusive of FIG. 34 (SEQ ID NO:56).

In a further aspect, the invention concerns an isolated PRO1359polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 32through 299 of FIG. 34 (SEQ ID NO:56).

In yet another aspect, the invention concerns an isolated PRO1359polypeptide, comprising the sequence of amino acid residues 32 to about299, inclusive of FIG. 34 (SEQ ID NO:56), or a fragment thereofsufficient to provide a binding site for an anti-PRO1359 antibody.Preferably, the PRO1359 fragment retains a qualitative biologicalactivity of a native PRO1359 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1359 polypeptide having the sequence ofamino acid residues from about 32 to about 299, inclusive of FIG. 34(SEQ ID NO:56), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1359 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1359 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1359 polypeptide, by contactingthe native PRO1359 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1359 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

18. PRO1190

A cDNA clone (DNA59586-1520) has been identified that encodes a novelpolypeptide designated in the present application as “PRO1190”, andwhich has homology to CDO protein.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1190 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1190 polypeptide having the sequence of amino acidresidues from about 1 to about 1115, inclusive of FIG. 36 (SEQ IDNO:58), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1190 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 340 and about3684, inclusive, of FIG. 35 (SEQ ID NO:58). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203288(DNA59586-1520), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203288 (DNA59586-1520).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 1115, inclusive of FIG. 36 (SEQ IDNO:58), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1190polypeptide having the sequence of amino acid residues from about 1 toabout 1115, inclusive of FIG. 36 (SEQ ID NO:58), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1190 polypeptide, with one or moreof its transmembrane domains deleted or inactivated variants, or iscomplementary to such encoding nucleic acid molecule. The transmembranedomains have been tentatively identified in the PRO1190 amino acidsequence shown in FIG. 36 (SEQ ID NO:58) as extending from about aminoacid position 16 to about amino acid position 30 and from about aminoacid position 854 to about amino acid position 879.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 1115, inclusive of FIG. 36 (SEQ ID NO:58), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1190 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1190polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1190 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 1115 of FIG. 36 (SEQ ID NO:58).

In another aspect, the invention concerns an isolated PRO1190polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 1115, inclusive of FIG. 36 (SEQ ID NO:58).

In a further aspect, the invention concerns an isolated PRO1190polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to1115 of FIG. 36 (SEQ ID NO:58).

In yet another aspect, the invention concerns an isolated PRO1190polypeptide, comprising the sequence of amino acid residues 1 to about1115, inclusive of FIG. 36 (SEQ ID NO:58), or a fragment thereofsufficient to provide a binding site for an anti-PRO190 antibody.Preferably, the PRO1190 fragment retains a qualitative biologicalactivity of a native PRO1190 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1190 polypeptide having the sequence ofamino acid residues from about 1 to about 1115, inclusive of FIG. 36(SEQ ID NO:58), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1190 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1190 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1190 polypeptide, by contactingthe native PRO1190 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1190 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

19. PRO1772

A cDNA clone (DNA59817-1703) has been identified, having homology tonucleic acid encoding peptidase enzymes, that encodes a novelpolypeptide, designated in the present application as “PRO1772”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1772 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1772 polypeptide having the sequence of amino acidresidues from about 1 or about 37 to about 487, inclusive of FIG. 38(SEQ ID NO:63), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1772 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 93 or about201 and about 1553, inclusive, of FIG. 37 (SEQ ID NO:62). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203470(DNA59817-1703) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203470 (DNA59817-1703).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 37 to about 487, inclusive of FIG. 38 (SEQ IDNO:63), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 415 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1772 polypeptide having the sequence of amino acidresidues from 1 or about 37 to about 487, inclusive of FIG. 38 (SEQ IDNO:63), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1772 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 36 in the sequence of FIG.38 (SEQ ID NO:63). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 313 to aboutamino acid position 331 in the PRO1772 amino acid sequence (FIG. 38, SEQID NO:63).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 37 to about 487, inclusive of FIG. 38 (SEQ ID NO:63), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1772 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 37 (SEQ ID NO:62).

In another embodiment, the invention provides isolated PRO1772polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1772 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 37 to about 487 of FIG. 38(SEQ ID NO:63).

In another aspect, the invention concerns an isolated PRO1772polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 37 to about 487, inclusive of FIG. 38 (SEQ ID NO:63).

In a further aspect, the invention concerns an isolated PRO1772polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 37 to about 487, inclusive of FIG. 38 (SEQ ID NO:63).

In yet another aspect, the invention concerns an isolated PRO1772polypeptide, comprising the sequence of amino acid residues 1 or about37 to about 487, inclusive of FIG. 38 (SEQ ID NO:63), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1772antibody. Preferably, the PRO1772 fragment retains a qualitativebiological activity of a native PRO1772 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1772 polypeptide having the sequence ofamino acid residues from about 1 or about 37 to about 487, inclusive ofFIG. 38 (SEQ ID NO:63), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b). (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1772 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1772 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1772 polypeptide by contactingthe native PRO1772 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1772 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

20. PRO1248

A cDNA clone (DNA60278-1530) has been identified, having homology tonucleic acid encoding PUT-2, that encodes a novel polypeptide,designated in the present application as “PRO1248”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1248 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1248 polypeptide having the sequence of amino acidresidues from about 1 or about 21 to about 183, inclusive of FIG. 40(SEQ ID NO:68), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1248 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 122 orabout 182 and about 670, inclusive, of FIG. 39 (SEQ ID NO:67).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203170(DNA60278-1530) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203170 (DNA60278-1530).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 21 to about 183, inclusive of FIG. 40 (SEQ IDNO:68), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1248 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 183, inclusive of FIG. 40 (SEQ IDNO:68), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1248 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 20 in the sequence of FIG.40 (SEQ ID NO:68). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 90 to about aminoacid position 112 in the PRO1248 amino acid sequence (FIG. 40, SEQ IDNO:68).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 21 to about 183, inclusive of FIG. 40 (SEQ ID NO:68), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1248 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 39 (SEQ ID NO:67).

In another embodiment, the invention provides isolated PRO1248polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1248 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 21 to about 183 of FIG. 40(SEQ ID NO:68).

In another aspect, the invention concerns an isolated PRO1248polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 21 to about 183, inclusive of FIG. 40 (SEQ ID NO:68).

In a further aspect, the invention concerns an isolated PRO1248polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 21 to about 183, inclusive of FIG. 40 (SEQ ID NO:68).

In yet another aspect, the invention concerns an isolated PRO1248polypeptide, comprising the sequence of amino acid residues 1 or about21 to about 183, inclusive of FIG. 40 (SEQ ID NO:68), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1248antibody. Preferably, the PRO1248 fragment retains a qualitativebiological activity of a native PRO1248 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1248 polypeptide having the sequence ofamino acid residues from about 1 or about 21 to about 183, inclusive ofFIG. 40 (SEQ ID NO:68), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1248 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1248 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1248 polypeptide by contactingthe native PRO1248 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1248 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

21. PRO1316

A cDNA clone (DNA60608-1577) has been identified, having homology toDickkopf that encodes a novel polypeptide, designated in the presentapplication as “PRO1316.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1316 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1316 polypeptide having the sequence of amino acidresidues from 1 or about 26 to about 259, inclusive of FIG. 42 (SEQ IDNO:70), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1316 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 281 and about987, inclusive, of FIG. 41 (SEQ ID NO:69). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203126(DNA60608-1577), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203126 (DNA60608-1577).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 26 to about 259, inclusive of FIG. 42 (SEQ IDNO:70), or the complement of the DNA of (a).

In a further aspect, the invention concern an isolated nucleic acidmolecule having at least 15 nucleotides which hybridizes under stringentconditions with (a) a DNA molecule having a identity with a regionspanning either from residues 1-454 or from residues 1095-3130 of theFIG. 41 (SEQ ID NO:69), or (b) the complement of the DNA molecule of(a). Alternatively, an isolated nucleic acid molecule having at least 15nucleotides having at least about 80% sequence identity, preferably atleast about 85% sequence identity, more preferably at least about 90%sequence identity, and most preferably at least about 95% sequenceidentity to: (a) a DNA molecule having a identity with a region spanningeither from residues 1-454 or from residues 1095-3130 of the FIG. 41(SEQ ID NO:69), or (b) the complement of the DNA molecule of (a).

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1316 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 to about amino acid position 25 in the sequence of FIG. 42(SEQ ID NO:70). An N-glycosylation site has been identified at position52 and a fungal Zn(2)-Cys(6) binuclear cluster has been identified atposition 99.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 26to about 259, inclusive of FIG. 42 (SEQ ID NO:70), or (b) the complementof the DNA of (a).

In another embodiment, the invention provides isolated PRO1316polypeptide encoded by any of the isolated nucleic acid sequences hereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1316 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 26 to 259 of FIG. 42 (SEQ ID NO:70).

In another aspect, the invention concerns an isolated PRO1316polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues26 to about 259, inclusive of FIG. 42 (SEQ ID NO:70).

In a further aspect, the invention concerns an isolated PRO1316polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 26 to259 of FIG. 42 (SEQ ID NO:70).

In yet another aspect, the invention concerns an isolated PRO1316polypeptide, comprising the sequence of amino acid residues 26 to about259, inclusive of FIG. 42 (SEQ ID NO:70), or a fragment thereofsufficient to provide a binding site for an anti-PRO1316 antibody.Preferably, the PRO1316 fragment retains a qualitative biologicalactivity of a native PRO1316 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1316 polypeptide having the sequence ofamino acid residues from about 26 to about 259, inclusive of FIG. 42(SEQ ID NO:70), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of the a native PRO1316 polypeptide. In a particularembodiment, the agonist or antagonist is an anti-PRO1316 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1316 polypeptide, by contactingthe native PRO1316 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1316 polypeptide, or an agonist or antagonist as hereinabove defined, in combination with a pharmaceutically acceptablecarrier.

22. PRO1197

A cDNA clone (DNA60611-1524) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1197.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1197 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1197 polypeptide having the sequence of amino acidresidues from 1 or about 25 to about 363, inclusive of FIG. 44 (SEQ IDNO:72), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1197 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 383 and about1399, inclusive, of FIG. 43 (SEQ ID NO:71). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203175(DNA60611-1524), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203175 (DNA60611-1524).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 25 to about 363, inclusive of FIG. 44 (SEQ IDNO:72), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1197polypeptide having the sequence of amino acid residues from about 25 toabout 363, inclusive of FIG. 44 (SEQ ID NO:72), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 25to about 363, inclusive of FIG. 44 (SEQ ID NO:72), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1197 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1197polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1197 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 25 through 363 of FIG. 44 (SEQ ID NO:72).

In another aspect, the invention concerns an isolated PRO1197polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues25 to about 363, inclusive of FIG. 44 (SEQ ID NO:72).

In a further aspect, the invention concerns an isolated PRO1197polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 25through 363 of FIG. 44 (SEQ ID NO:72).

In yet another aspect, the invention concerns an isolated PRO1197polypeptide, comprising the sequence of amino acid residues 25 to about363, inclusive of FIG. 44 (SEQ ID NO:72), or a fragment thereofsufficient to provide a binding site for an anti-PRO1197 antibody.Preferably, the PRO1197 fragment retains a qualitative biologicalactivity of a native PRO1197 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1197 polypeptide having the sequence ofamino acid residues from about 25 to about 363, inclusive of FIG. 44(SEQ ID NO:72), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1197 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1197 antibody.

23. PRO1293

A cDNA clone (DNA60618-1557) has been identified, having homology tonucleic acid encoding an immunoglobulin heavy chain variable regionprotein that encodes a novel polypeptide, designated in the presentapplication as “PRO1293”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1293 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1293 polypeptide having the sequence of amino acidresidues from about 1 or about 20 to about 341, inclusive of FIG. 46(SEQ ID NO:77), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1293 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 37 or about94 and about 1059, inclusive, of FIG. 45 (SEQ ID NO:76). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203292(DNA60618-1557) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203292 (DNA60618-1557).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 20 to about 341, inclusive of FIG. 46 (SEQ IDNO:77), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1293 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 341, inclusive of FIG. 46 (SEQ IDNO:77), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1293 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 19 in the sequence of FIG.46 (SEQ ID NO:77). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 237 to aboutamino acid position 262 in the PRO1293 amino acid sequence (FIG. 46, SEQID NO:77).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 20 to about 341, inclusive of FIG. 46 (SEQ ID NO:77), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1293 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 45 (SEQ ID NO:76).

In another embodiment, the invention provides isolated PRO1293polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1293 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 20 to about 341 of FIG. 46(SEQ ID NO:77).

In another aspect, the invention concerns an isolated PRO1293polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 20 to about 341, inclusive of FIG. 46 (SEQ ID NO:77).

In a further aspect, the invention concerns an isolated PRO1293polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 20 to about 341, inclusive of FIG. 46 (SEQ ID NO:77).

In yet another aspect, the invention concerns an isolated PRO1293polypeptide, comprising the sequence of amino acid residues 1 or about20 to about 341, inclusive of FIG. 46 (SEQ ID NO:77), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1293antibody. Preferably, the PRO1293 fragment retains a qualitativebiological activity of a native PRO1293 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1293 polypeptide having the sequence ofamino acid residues from about 1 or about 20 to about 341, inclusive ofFIG. 46 (SEQ ID NO:77), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1293 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1293 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1293 polypeptide by contactingthe native PRO1293 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1293 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

24. PRO1380

A cDNA clone (DNA60740-1615) has been identified that encodes a novelmulti-span transmembrane polypeptide designated in the presentapplication as “PRO1380”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1380 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1380 polypeptide having the sequence of amino acidresidues from about 1 to about 470, inclusive of FIG. 48 (SEQ ID NO:79),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1380 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 36 and about1460, inclusive, of FIG. 47 (SEQ ID NO:78). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203456(DNA60740-1615), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203456 (DNA60740-1615).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 470, inclusive of FIG. 48 (SEQ IDNO:79), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1380polypeptide having the sequence of amino acid residues from about 1 toabout 470, inclusive of FIG. 48 (SEQ ID NO:79), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1380 polypeptide, and its solublevariants (i.e. one or more transmembrane domains deleted orinactivated), or is complementary to such encoding nucleic acidmolecule. Transmembrane domains have been tentatively identified atabout the following amino acid positions: 50-74, 105-127, 135-153,163-183, 228-252, 305-330, and 448-472 in the PRO1380 amino acidsequence (FIG. 48, SEQ ID NO:79).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 470, inclusive of FIG. 48 (SEQ ID NO:79), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1380 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1380polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1380 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 470 of FIG. 48 (SEQ ID NO:79).

In another aspect, the invention concerns an isolated PRO1380polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 470, inclusive of FIG. 48 (SEQ ID NO:79).

In a further aspect, the invention concerns an isolated PRO1380polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to470 of FIG. 48 (SEQ ID NO:79).

In yet another aspect, the invention concerns an isolated PRO1380polypeptide, comprising the sequence of amino acid residues 1 to about470, inclusive of FIG. 48 (SEQ ID NO:79), or a fragment thereofsufficient to provide a binding site for an anti-PRO1380 antibody.Preferably, the PRO1380 fragment retains a qualitative biologicalactivity of a native PRO1380 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1380 polypeptide having the sequence ofamino acid residues from about 1 to about 470, inclusive of FIG. 48 (SEQID NO:79), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

25. PRO1265

A cDNA clone (DNA60764-1533) has been identified that encodes a novelpolypeptide having homology to the FIG. 1 polypeptide and designated inthe present application as “PRO1265.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1265 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1265 polypeptide having the sequence of amino acidresidues from 1 or about about 22 to about 567, inclusive of FIG. 50(SEQ ID NO:84), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1265 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 142 and about1779, inclusive, of FIG. 49 (SEQ ID NO:83). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203452(DNA60764-1533), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203452 (DNA60764-1533).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 22 to about 567, inclusive of FIG. 50 (SEQ IDNO:84), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1265polypeptide having the sequence of amino acid residues from about 22 toabout 567, inclusive of FIG. 50 (SEQ ID NO:84), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1265 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 21 in the sequence of FIG. 50 (SEQ IDNO:84).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 22to about 567, inclusive of FIG. 50 (SEQ ID NO:84), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1265 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1265polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1265 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 or about 22 to 567 of FIG. 50 (SEQ IDNO:84).

In another aspect, the invention concerns an isolated PRO1265polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues22 to about 567, inclusive of FIG. 50 (SEQ ID NO:84).

In a further aspect, the invention concerns an isolated PRO1265polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 22 to567 of FIG. 50 (SEQ ID NO:84).

In yet another aspect, the invention concerns an isolated PRO1265polypeptide, comprising the sequence of amino acid residues 22 to about567, inclusive of FIG. 50 (SEQ ID NO:84), or a fragment thereofsufficient to provide a binding site for an anti-PRO1265 antibody.Preferably, the PRO1265 fragment retains a qualitative biologicalactivity of a native PRO1265 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1265 polypeptide having the sequence ofamino acid residues from about 22 to about 567, inclusive of FIG. 50(SEQ ID NO:84), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

26. PRO1250

A cDNA clone (DNA60775-1532) has been identified, having homology tonucleic acid encoding long chain fatty acid CoA ligase that encodes anovel polypeptide, designated in the present application as “PRO1250”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1250 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1250 polypeptide having the sequence of amino acidresidues from about 1 to about 739, inclusive of FIG. 52 (SEQ ID NO:86),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1250 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 74 andabout 2290, inclusive, of FIG. 51 (SEQ ID NO:85). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203173(DNA60775-1532) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203173 (DNA60775-1532).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 to about 739, inclusive of FIG. 52 (SEQ ID NO:86), or(b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1250 polypeptide having the sequence of amino acidresidues from 1 to about 739, inclusive of FIG. 52 (SEQ ID NO:86), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1250 polypeptide, with or withoutthe initiating methionine, and its soluble, i.e., transmembrane domaindeleted or inactivated variants, or is complementary to such encodingnucleic acid molecule. The type II transmembrane domain has beententatively identified as extending from about amino acid position 61 toabout amino acid position 80 in the PRO1250 amino acid sequence (FIG.52, SEQ ID NO:86).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 739, inclusive of FIG. 52 (SEQ ID NO:86), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1250 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 51 (SEQ ID NO:85).

In another embodiment, the invention provides isolated PRO1250polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1250 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 to about 739 of FIG. 52 (SEQ IDNO:86).

In another aspect, the invention concerns an isolated PRO1250polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 739, inclusive of FIG. 52 (SEQ ID NO:86).

In a further aspect, the invention concerns an isolated PRO1250polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toabout 739, inclusive of FIG. 52 (SEQ ID NO:86).

In yet another aspect, the invention concerns an isolated PRO1250polypeptide, comprising the sequence of amino acid residues 1 to about739, inclusive of FIG. 52 (SEQ ID NO:86), or a fragment thereofsufficient to provide a binding site for an anti-PRO1250 antibody.Preferably, the PRO1250 fragment retains a qualitative biologicalactivity of a native PRO1250 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1250 polypeptide having the sequence ofamino acid residues from about 1 to about 739, inclusive of FIG. 52 (SEQID NO:86), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1250 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1250 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1250 polypeptide by contactingthe native PRO1250 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1250 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

27. PRO1475

A cDNA clone (DNA61185-1646) has been identified, having homology tonucleic acid encoding an N-acetylglucosaminyltransferase that encodes anovel polypeptide, designated in the present application as “PRO1475”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1475 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1475 polypeptide having the sequence of amino acidresidues from about 1 to about 660, inclusive of FIG. 54 (SEQ ID NO:88),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1475 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 130 andabout 2109, inclusive, of FIG. 53 (SEQ ID NO:87). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203464(DNA61185-1646) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203464 (DNA61185-1646).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 to about 660, inclusive of FIG. 54 (SEQ ID NO:88), or(b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 180 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1475 polypeptide having the sequence of amino acidresidues from 1 to about 660, inclusive of FIG. 54 (SEQ ID NO:88), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1475 polypeptide, with or withoutthe initiating methionine, and its soluble, i.e., transmembrane domaindeleted or inactivated variants, or is complementary to such encodingnucleic acid molecule. The transmembrane domain has been tentativelyidentified as extending from about amino acid position 38 to about aminoacid position 55 in the PRO1475 amino acid sequence (FIG. 54, SEQ IDNO:88).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 660, inclusive of FIG. 54 (SEQ ID NO:88), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1475 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 53 (SEQ ID NO:87).

In another embodiment, the invention provides isolated PRO1475polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1475 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 to about 660 of FIG. 54 (SEQ IDNO:88).

In another aspect, the invention concerns an isolated PRO1475polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 660, inclusive of FIG. 54 (SEQ ID NO:88).

In a further aspect, the invention concerns an isolated PRO1475polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toabout 660, inclusive of FIG. 54 (SEQ ID NO:88).

In yet another aspect, the invention concerns an isolated PRO1475polypeptide, comprising the sequence of amino acid residues 1 to about660, inclusive of FIG. 54 (SEQ ID NO:88), or a fragment thereofsufficient to provide a binding site for an anti-PRO1475 antibody.Preferably, the PRO1475 fragment retains a qualitative biologicalactivity of a native PRO1475 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1475 polypeptide having the sequence ofamino acid residues from about 1 to about 660, inclusive of FIG. 54 (SEQID NO:88), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1475 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1475 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1475 polypeptide by contactingthe native PRO1475 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1475 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

28. PRO1377

A cDNA clone (DNA61608-1606) has been identified that encodes a novelmulti-span transmembrane polypeptide designated in the presentapplication as “PRO1377.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1377 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1377 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 307, inclusive of FIG. 56 (SEQ IDNO:95), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1377 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 203 and about1069, inclusive, of FIG. 55 (SEQ ID NO:94). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203239(DNA61608-1606), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203239 (DNA61608-1606).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 307, inclusive of FIG. 56 (SEQ IDNO:95), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1377polypeptide having the sequence of amino acid residues from about 19 toabout 307, inclusive of FIG. 56 (SEQ ID NO:95), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1377 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and oneor more of its transmembrane domains deleted or inactivated, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 18 in the sequence of FIG. 56 (SEQ IDNO:95). Transmembrane domain has been tentatively identified asextending from about amino acid positions 37-56, 106-122, 211-20,240-260, and 288-304 in the PRO1377 amino acid sequence (FIG. 56, SEQ IDNO:95).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 307, inclusive of FIG. 56 (SEQ ID NO:95), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1377 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1377polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1377 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 to 307 of FIG. 56 (SEQ ID NO:95).

In another aspect, the invention concerns an isolated PRO1377polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 307, inclusive of FIG. 56 (SEQ ID NO:95).

In a further aspect, the invention concerns an isolated PRO1377polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19 to307 of FIG. 56 (SEQ ID NO:95).

In yet another aspect, the invention concerns an isolated PRO1377polypeptide, comprising the sequence of amino acid residues 19 to about307, inclusive of FIG. 56 (SEQ ID NO:95), or a fragment thereofsufficient to provide a binding site for an anti-PRO1377 antibody.Preferably, the PRO1377 fragment retains a qualitative biologicalactivity of a native PRO1377 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1377 polypeptide having the sequence ofamino acid residues from about 19 to about 307, inclusive of FIG. 56(SEQ ID NO:95), or (b) the complement of the DNA molecule of (a), and ifthe test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

29. PRO1326

A cDNA clone (DNA62808-1582) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1326.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1326 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1326 polypeptide having the sequence of amino acidresidues from 1 or about 30 to about 401, inclusive of FIG. 58 (SEQ IDNO:100), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1326 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 199 and about1314, inclusive, of FIG. 57 (SEQ ID NO:99). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203358(DNA62808-1582), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203358 (DNA62808-1582).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 30 to about 401, inclusive of FIG. 58 (SEQ IDNO:100), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1326polypeptide having the sequence of amino acid residues from about 30 toabout 401, inclusive of FIG. 58 (SEQ ID NO:100), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1326 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 29 in the sequence of FIG. 58 (SEQ IDNO:100).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 30to about 401, inclusive of FIG. 58 (SEQ ID NO:100), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1326 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1326polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1326 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 30 to 401 of FIG. 58 (SEQ ID NO:100).

In another aspect, the invention concerns an isolated PRO1326polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues30 to about 401, inclusive of FIG. 58 (SEQ ID NO:100).

In a further aspect, the invention concerns an isolated PRO1326polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 30 to401 of FIG. 58 (SEQ ID NO:100).

In yet another aspect, the invention concerns an isolated PRO1326polypeptide, comprising the sequence of amino acid residues 30 to about401, inclusive of FIG. 58 (SEQ ID NO:100), or a fragment thereofsufficient to provide a binding site for an anti-PRO1326 antibody.Preferably, the PRO1326 fragment retains a qualitative biologicalactivity of a native PRO1326 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1326 polypeptide having the sequence ofamino acid residues from about 30 to about 401, inclusive of FIG. 58(SEQ ID NO:100), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

30. PRO1249

A cDNA clone (DNA62809-1531) has been identified that encodes a noveltransmembrane polypeptide, designated in the present application as“PRO1249”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1249 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1249 polypeptide having the sequence of amino acidresidues from about 1 or about 17 to about 1089, inclusive of FIG. 60(SEQ ID NO:102), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1249 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 3 or about51 and about 3269, inclusive, of FIG. 59 (SEQ ID NO:101). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203237(DNA62809-1531) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203237 (DNA62809-1531).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 17 to about 1089, inclusive of FIG. 60 (SEQ IDNO:102), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1249 polypeptide having the sequence of amino acidresidues from 1 or about 17 to about 1089, inclusive of FIG. 60 (SEQ IDNO:102), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1249 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 16 in the sequence of FIG.60 (SEQ ID NO:102). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 317 to aboutamino acid position 341, from about amino acid position 451 to aboutamino acid position 470, from about amino acid position 481 to aboutamino acid position 500, from about amino acid position 510 to aboutamino acid position 527, from about amino acid position 538 to aboutamino acid position 555, from about amino acid position 831 to aboutamino acid position 850, from about amino acid position 1016 to aboutamino acid position 1034 and from about amino acid position 1052 toabout amino acid position 1070 in the PRO1249 amino acid sequence (FIG.60, SEQ ID NO:102).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 17 to about 1089, inclusive of FIG. 60 (SEQ ID NO:102), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1249 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 59 (SEQ ID NO:101).

In another embodiment, the invention provides isolated PRO1249polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1249 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 17 to about 1089 of FIG. 60(SEQ ID NO:102).

In another aspect, the invention concerns an isolated PRO1249polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 17 to about 1089, inclusive of FIG. 60 (SEQ ID NO:102).

In a further aspect, the invention concerns an isolated PRO1249polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 17 to about 1089, inclusive of FIG. 60 (SEQ ID NO:102).

In yet another aspect, the invention concerns an isolated PRO1249polypeptide, comprising the sequence of amino acid residues 1 or about17 to about 1089, inclusive of FIG. 60 (SEQ ID NO:102), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1249antibody. Preferably, the PRO1249 fragment retains a qualitativebiological activity of a native PRO1249 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1249 polypeptide having the sequence ofamino acid residues from about 1 or about 17 to about 1089, inclusive ofFIG. 60 (SEQ ID NO:102), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

31. PRO1315

A cDNA clone (DNA62815-1576) has been identified, having homology tonucleic acid encoding cytokine receptor family-4 proteins that encodes anovel polypeptide, designated in the present application as “PRO1315”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1315 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1315 polypeptide having the sequence of amino acidresidues from about 1 or about 29 to about 442, inclusive of FIG. 62(SEQ ID NO:104), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1315 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 121 orabout 205 and about 1446, inclusive, of FIG. 61 (SEQ ID NO:103).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203247(DNA62815-1576) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203247 (DNA62815-1576).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 29 to about 442, inclusive of FIG. 62 (SEQ IDNO:104), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 500 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1315 polypeptide having the sequence of amino acidresidues from 1 or about 29 to about 442, inclusive of FIG. 62 (SEQ IDNO:104), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1315 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 28 in the sequence of FIG.62 (SEQ ID NO:104). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 140 to aboutamino acid position 163 in the PRO1315 amino acid sequence (FIG. 62, SEQID NO:104).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 29 to about 442, inclusive of FIG. 62 (SEQ ID NO:104), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1315 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 61 (SEQ ID NO:103).

In another embodiment, the invention provides isolated PRO1315polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1315 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 29 to about 442 of FIG. 62(SEQ ID NO:104).

In another aspect, the invention concerns an isolated PRO1315polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 29 to about 442, inclusive of FIG. 62 (SEQ ID NO:104).

In a further aspect, the invention concerns an isolated PRO1315polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 29 to about 442, inclusive of FIG. 62 (SEQ ID NO:104).

In yet another aspect, the invention concerns an isolated PRO1315polypeptide, comprising the sequence of amino acid residues 1 or about29 to about 442, inclusive of FIG. 62 (SEQ ID NO:104), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1315antibody. Preferably, the PRO1315 fragment retains a qualitativebiological activity of a native PRO1315 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1315 polypeptide having the sequence ofamino acid residues from about 1 or about 29 to about 442, inclusive ofFIG. 62 (SEQ ID NO:104), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1315 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1315 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1315 polypeptide by contactingthe native PRO1315 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1315 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

32. PRO1599

A cDNA clone (DNA62845-1684) has been identified that encodes a novelpolypeptide having homology to Granzyme M and designated in the presentapplication as “PRO1599.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1599 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1599 polypeptide having the sequence of amino acidresidues from 1 or about 31 to about 283, inclusive of FIG. 64 (SEQ IDNO:111), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1599 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 159 and about917, inclusive, of FIG. 63 (SEQ ID NO:110). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by te human protein cDNA in ATCC Deposit No. 203361(DNA62845-1684), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203361 (DNA62845-1684).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 31 to about 283, inclusive of FIG. 64 (SEQ IDNO:111), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1599polypeptide having the sequence of amino acid residues from about 31 toabout 283, inclusive of FIG. 64 (SEQ ID NO:111), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1599 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 30 in the sequence of FIG. 64 (SEQ IDNO:111).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 31to about 283, inclusive of FIG. 64 (SEQ ID NO:111), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1599 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1599polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1599 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 31 to 283 of FIG. 64 (SEQ ID NO:111).

In another aspect, the invention concerns an isolated PRO1599polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues31 to about 283, inclusive of FIG. 64 (SEQ ID NO:111).

In a further aspect, the invention concerns an isolated PRO1599polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 31 to283 of FIG. 64 (SEQ ID NO:111).

In yet another aspect, the invention concerns an isolated PRO1599polypeptide, comprising the sequence or amino acid residues 31 to about283, inclusive of FIG. 64 (SEQ ID NO:111), or a fragment thereofsufficient to provide a binding site for an anti-PRO1599 antibody.Preferably, the PRO1599 fragment retains a qualitative biologicalactivity of a native PRO1599 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1599 polypeptide having the sequence ofamino acid residues from about 31 to about 283, inclusive of FIG. 64(SEQ ID NO:111), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1599 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1599 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1599 polypeptide, by contactingthe native PRO1599 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1599 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

33. PRO1430

A cDNA clone (DNA64842-1632) has been identified that encodes a novelpolypeptide having homology to reductase proteins, designated in thepresent application as “PRO1430.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1430 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1430 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 331, inclusive of FIG. 66 (SEQ IDNO:116), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1430 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 33 and about1074, inclusive, of FIG. 65 (SEQ ID NO:115). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203278(DNA64842-1632), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203278 (DNA64842-1632).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 18 to about 331, inclusive of FIG. 66 (SEQ IDNO:116), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 and produced by hybridizing a test DNA molecule understringent conditions with (a) a DNA molecule encoding a PRO1430polypeptide having the sequence of amino acid residues from about 18 toabout 331, inclusive of FIG. 66 (SEQ ID NO:116), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1430 polypeptide, with or withoutthe N-terminal signal sequence, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from amino acid position 1 through about aminoacid position 17 in the sequence of FIG. 66 (SEQ ID NO:116).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 18to about 331, inclusive of FIG. 66 (SEQ ID NO:116), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1430 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1430polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1430 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 18 to 331 of FIG. 66 (SEQ ID NO:116).

In another aspect, the invention concerns an isolated PRO1430polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues18 to about 331, inclusive of FIG. 66 (SEQ ID NO:116).

In a further aspect, the invention concerns an isolated PRO1430polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 18 to331 of FIG. 66 (SEQ ID NO:116).

In yet another aspect, the invention concerns an isolated PRO1430polypeptide, comprising the sequence of amino acid residues 18 to about331, inclusive of FIG. 66 (SEQ ID NO:116), or a fragment thereofsufficient to provide a binding site for an anti-PRO1430 antibody.Preferably, the PRO1430 fragment retains a qualitative biologicalactivity of a native PRO1430 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1430 polypeptide having the sequence ofamino acid residues from about 18 to about 331, inclusive of FIG. 66(SEQ ID NO:116), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1430 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1430 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1430 polypeptide, by contactingthe native PRO1430 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1430 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

34. PRO1374

A cDNA clone (DNA64849-1604) has been identified that encodes a novelpolypeptide having sequence identity with P4HA and designated in thepresent application as “PRO1374.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1374 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1374 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 544, inclusive of FIG. 68 (SEQ IDNO:118), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1374 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 78 and about1652, inclusive, of FIG. 67 (SEQ ID NO:117). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203468(DNA64849-1604), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203468 (DNA64849-1604).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having a leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 20 to about 544, inclusive of FIG. 68 (SEQ IDNO:118), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1374polypeptide having the sequence of amino acid residues from about 20 toabout 544, inclusive of FIG. 68 (SEQ ID NO:118), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 20to about 544, inclusive of FIG. 68 (SEQ ID NO:118), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1374 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments arc from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1374polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1374 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 20 through 544 of FIG. 68 (SEQ ID NO:118).

In another aspect, the invention concerns an isolated PRO1374polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues20 to about 544, inclusive of FIG. 68 (SEQ ID NO:118).

In a further aspect, the invention concerns an isolated PRO1374polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 20through 544 of FIG. 68 (SEQ ID NO:118).

In yet another aspect, the invention concerns an isolated PRO1374polypeptide, comprising the sequence of amino acid residues 20 to about544, inclusive of FIG. 68 (SEQ ID NO:118), or a fragment thereofsufficient to provide a binding site for an anti-PRO1374 antibody.Preferably, the PRO1374 fragment retains a qualitative biologicalactivity of a native PRO1374 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1374 polypeptide having the sequence ofamino acid residues from about 20 to about 544, inclusive of FIG. 68(SEQ ID NO:118), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1374 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1374 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1374 polypeptide, by contactingthe native PRO1374 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1374 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

35. PRO1311

A cDNA clone (DNA64863-1573) has been identified that encodes a noveltetraspan polypeptide designated in the present application as“PRO1311”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1311 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1311 polypeptide having the sequence of amino acidresidues from 1 or about 45 to about 294, inclusive of FIG. 70 (SEQ IDNO:123), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1311 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 327 and about1076, inclusive, of FIG. 69 (SEQ ID NO:122). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203251(DNA64863-1573), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203251 (DNA64863-1573).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 45 to about 294, inclusive of FIG. 70 (SEQ IDNO:123), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1311polypeptide having the sequence of amino acid residues from about 45 toabout 294, inclusive of FIG. 70 (SEQ ID NO:123), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1311 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domains deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 44 in the sequence of FIG.70 (SEQ ID NO:123). Four transmembrane domains has been tentativelyidentified as extending from about amino acid 22-42, 57-85, 94-116, and230-257 in the PRO1311 amino acid sequence (FIG. 70, SEQ ID NO:123).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 45to about 294, inclusive of FIG. 70 (SEQ ID NO:123), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1311 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1311polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1311 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 45 to 294 of FIG. 70 (SEQ ID NO:123).

In another aspect, the invention concerns an isolated PRO1311polypeptide, comprising an amino acid 110 sequence having at least about80% sequence identity, preferably at least about 85% sequence identity,more preferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues45 to about 294, inclusive of FIG. 70 (SEQ ID NO:123).

In a further aspect, the invention concerns an isolated PRO1311polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 45 to294 of FIG. 70 (SEQ ID NO:123).

In yet another aspect, the invention concerns an isolated PRO1311polypeptide, comprising the sequence of amino acid residues 45 to about294, inclusive of FIG. 70 (SEQ ID NO:123), or a fragment thereofsufficient to provide a binding site for an anti-PRO1311 antibody.Preferably, the PRO1311 fragment retains a qualitative biologicalactivity of a native PRO1311 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1311 polypeptide having the sequence ofamino acid residues from about 45 to about 294, inclusive of FIG. 70(SEQ ID NO:123), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

36. PRO1357

A cDNA clone (DNA64881-1602) has been identified, having homology tonucleic acid encoding the von Ebner minor salivary gland protein thatencodes a novel polypeptide, designated in the present application as“PRO1357”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1357 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1357 polypeptide having the sequence of amino acidresidues from about 1 or about 22 to about 484, inclusive of FIG. 72(SEQ ID NO:128), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1357 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 74 or about137 and about 1525, inclusive, of FIG. 71 (SEQ ID NO:127). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203240(DNA64881-1602) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203240 (DNA64881-1602).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 22 to about 484, inclusive of FIG. 72 (SEQ IDNO:128), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 40 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1357 polypeptide having the sequence of amino acidresidues from 1 or about 22 to about 484, inclusive of FIG. 72 (SEQ IDNO:128), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1357 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 21 in the sequence of FIG. 72(SEQ ID NO:128).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 22 to about 484, inclusive of FIG. 72 (SEQ ID NO:128), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1357 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 71 (SEQ ID NO:127).

In another embodiment, the invention provides isolated PRO1357polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1357 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 22 to about 484 of FIG. 72(SEQ ID NO:128).

In another aspect, the invention concerns an isolated PRO1357polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 22 to about 484, inclusive of FIG. 72 (SEQ ID NO:128).

In a further aspect, the invention concerns an isolated PRO1357polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 22 to about 484, inclusive of FIG. 72 (SEQ ID NO:128).

In yet another aspect, the invention concerns an isolated PRO1357polypeptide, comprising the sequence of amino acid residues 1 or about22 to about 484, inclusive of FIG. 72 (SEQ ID NO:128), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1357antibody. Preferably, the PRO1357 fragment retains a qualitativebiological activity of a native PRO1357 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1357 polypeptide having the sequence ofamino acid residues from about 1 or about 22 to about 484, inclusive ofFIG. 72 (SEQ ID NO:128), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1357 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1357 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1357 polypeptide by contactingthe native PRO1357 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1357 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

37. PRO1244

A cDNA clone (DNA64883-1526) has been identified that encodes a novelpolypeptide having homology to Implantation-Associated Protein anddesignated in the present application as “PRO1244.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1244 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1244 polypeptide having the sequence of amino acidresidues from 1 or about 30 to about 335, inclusive of FIG. 74 (SEQ IDNO:130), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1244 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 96 and about1013, inclusive, of FIG. 73 (SEQ ID NO:129). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203253(DNA64883-1526), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203253 (DNA64883-1526).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 30 to about 335, inclusive of FIG. 74 (SEQ IDNO:130), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1244polypeptide having the sequence of amino acid residues from about 30 toabout 335, inclusive of FIG. 74 (SEQ ID NO:130), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1244 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domains deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 29 in the sequence of FIG.74 (SEQ ID NO:130). The transmembrane domains have been tentativelyidentified in the PRO1244 amino acid sequence at about the followingamino acid regions: 183-205, 217-137, 271-287, and 301-321.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 30to about 335, inclusive of FIG. 74 (SEQ ID NO:130), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1244 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1244polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1244 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 30 to 335 of FIG. 74 (SEQ ID NO:130).

In another aspect, the invention concerns an isolated PRO1244polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues30 to about 335, inclusive of FIG. 74 (SEQ ID NO:130).

In a further aspect, the invention concerns an isolated PRO1244polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 30 to335 of FIG. 74 (SEQ ID NO:130).

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1244 polypeptide having the sequence ofamino acid residues from about 30 to about 335, inclusive of FIG. 74(SEQ ID NO:130), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1244 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1244 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1244 polypeptide, by contactingthe native PRO1244 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1244 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

38. PRO1246

A cDNA clone (DNA64885-1529) has been identified, having homology tonucleic acid encoding bone-related sulphatase that encodes a novelpolypeptide, designated in the present application as “PRO1246”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1246 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1246 polypeptide having the sequence of amino acidresidues from about 1 or about 16 to about 536, inclusive of FIG. 76(SEQ ID NO:132), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1246 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 119 orabout 164 and about 1726, inclusive, of FIG. 75 (SEQ ID NO:131).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203457(DNA64885-1529) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203457 (DNA64885-1529).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 16 to about 536, inclusive of FIG. 76 (SEQ IDNO:132), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1246 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 536, inclusive of FIG. 76 (SEQ IDNO:132), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1246 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 16 in the sequence of FIG. 76(SEQ ID NO:132).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 16 to about 536, inclusive of FIG. 76 (SEQ ID NO:132), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1246 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 75 (SEQ ID NO:131).

In another embodiment, the invention provides isolated PRO1246polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1246 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 16 to about 536 of FIG. 76(SEQ ID NO:132).

In another aspect, the invention concerns an isolated PRO1246polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 16 to about 536, inclusive of FIG. 76 (SEQ ID NO:132).

In a further aspect, the invention concerns an isolated PRO1246polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 16 to about 536, inclusive of FIG. 76 (SFQ ID NO:132).

In yet another aspect, the invention concerns an isolated PRO1246polypeptide, comprising the sequence of amino acid residues 1 or about16 to about 536, inclusive of FIG. 76 (SEQ ID NO:132), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1246antibody. Preferably, the PRO1246 fragment retains a qualitativebiological activity of a native PRO1246 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1246 polypeptide having the sequence ofamino acid residues from about 1 or about 16 to about 536, inclusive ofFIG. 76 (SEQ ID NO:132), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1246 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1246 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1246 polypeptide by contactingthe native PRO1246 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1246 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

39. PRO1356

A cDNA clone (DNA64886-1601) has been identified, having homology tonucleic acid encoding clostridium perfringens enterotoxin receptor, thatencodes a novel polypeptide, designated in the present application as“PRO1356”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1356 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1356 polypeptide having the sequence of amino acidresidues from about 1 or about 25 to about 230, inclusive of FIG. 78(SEQ ID NO:134), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1356 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 122 orabout 194 and about 811, inclusive, of FIG. 77 (SEQ ID NO:133).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203241(DNA64886-1601) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203241 (DNA64886-1601).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 25 to about 230, inclusive of FIG. 78 (SEQ IDNO:134), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 20 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1356 polypeptide having the sequence of amino acidresidues from 1 or about 25 to about 230, inclusive of FIG. 78 (SEQ IDNO:134), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1356 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 24 in the sequence of FIG.78 (SEQ ID NO:134). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 82 to about aminoacid position 102, from about amino acid position 117 to about aminoacid position 140 and from about amino acid position 163 to about aminoacid position 182 in the PRO1356 amino acid sequence (FIG. 78, SEQ IDNO:134).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 25 to about 230, inclusive of FIG. 78 (SEQ ID NO:134), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1356 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 77. (SEQ ID NO:133).

In another embodiment, the invention provides isolated PRO1356polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1356 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 25 to about 230 of FIG. 78(SEQ ID NO:134).

In another aspect, the invention concerns an isolated PRO1356polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 25 to about 230, inclusive of FIG. 78 (SEQ ID NO:134).

In a further aspect, the invention concerns an isolated PRO1356polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 25 to about 230, inclusive of FIG. 78 (SEQ ID NO:134).

In yet another aspect, the invention concerns an isolated PRO1356polypeptide, comprising the sequence of amino acid residues 1 or about25 to about 230, inclusive of FIG. 78 (SEQ ID NO:134), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1356antibody. Preferably, the PRO1356 fragment retains a qualitativebiological activity of a native PRO1356 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1356 polypeptide having the sequence ofamino acid residues from about 1 or about 25 to about 230, inclusive ofFIG. 78 (SEQ ID NO:134), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1356 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1356 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1356 polypeptide by contactingthe native PRO1356 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1356 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

40. PRO1275

A cDNA clone (DNA64888-1542) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1275.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1275 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1275 polypeptide having the sequence of amino acidresidues from about 26 to about 119, inclusive of FIG. 80 (SEQ IDNO:136), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1275 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 112 and about393, inclusive, of FIG. 79 (SEQ ID NO:135). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203249(DNA64888-1542), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203249 (DNA64888-1542).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 26 to about 119, inclusive of FIG. 80 (SEQ IDNO:136), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1275polypeptide having the sequence of amino acid residues from about 26 toabout 119, inclusive of FIG. 80 (SEQ ID NO:136), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 26to about 119, inclusive of FIG. 80 (SEQ ID NO:136), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1275 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1275polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1275 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 26 through 119 of FIG. 80 (SEQ ID NO:136).

In another aspect, the invention concerns an isolated PRO1275polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues26 to about 119, inclusive of FIG. 80 (SEQ ID NO:136).

In a further aspect, the invention concerns an isolated PRO1275polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 26through 119 of FIG. 80 (SEQ ID NO:136).

In yet another aspect, the invention concerns an isolated PRO1275polypeptide, comprising the sequence of amino acid residues 26 to about119, inclusive of FIG. 80 (SEQ ID NO:136), or a fragment thereofsufficient to provide a binding site for an anti-PRO1275 antibody.Preferably, the PRO1275 fragment retains a qualitative biologicalactivity of a native PRO1275 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1275 polypeptide having the sequence ofamino acid residues from about 26 to about 119, inclusive of FIG. 80(SEQ ID NO:136), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1275 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1275 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1275 polypeptide, by contactingthe native PRO1275 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1275 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

41. PRO1274

A cDNA clone (DNA64889-1541) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1274.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1274 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1274 polypeptide having the sequence of amino acidresidues from 1 or about 25 to about 110, inclusive of FIG. 82 (SEQ IDNO:138), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1274 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 96 and about353, inclusive, of FIG. 81 (SEQ ID NO:137). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203250(DNA64889-1541), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203250 (DNA64889-1541).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 25 to about 110, inclusive of FIG. 82 (SEQ IDNO:138), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1274polypeptide having the sequence of amino acid residues from about 25 toabout 110, inclusive of FIG. 82 (SEQ ID NO:138), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 25to about 110, inclusive of FIG. 82 (SEQ ID NO:138), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1274 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1274polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1274 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 25 through 110 of FIG. 82 (SEQ ID NO:138).

In another aspect, the invention concerns an isolated PRO1274polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues25 to about 110, inclusive of FIG. 82 (SEQ ID NO:138).

In a further aspect, the invention concerns an isolated PRO1274polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 25through 110 of FIG. 82 (SEQ ID NO:138).

In yet another aspect, the invention concerns an isolated PRO1274polypeptide, comprising the sequence of amino acid residues 25 to about110, inclusive of FIG. 82 (SEQ ID NO:138), or a fragment thereofsufficient to provide a binding site for an anti-PRO1274 antibody.Preferably, the PRO1274 fragment retains a qualitative biologicalactivity of a native PRO1274 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1274 polypeptide having the sequence ofamino acid residues from about 25 to about 110, inclusive of FIG. 82(SEQ ID NO:138), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1274 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1274 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1274 polypeptide, by contactingthe native PRO1274 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1274 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

42. PRO1412

A cDNA clone (DNA64897-1628) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1412.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1412 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1412 polypeptide having the sequence of amino acidresidues from 1 or about 29 to about 311, inclusive of FIG. 84 (SEQ IDNO:140), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1412 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 226 and about1074, inclusive, of FIG. 83 (SEQ ID NO:139). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the sane maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No.203216(DNA64897-1628), or (b) the complement of the DNA molecule of (a).In a preferred embodiment, the nucleic acid comprises a DNA encoding thesame mature polypeptide encoded by the human protein cDNA in ATCCDeposit No. 203216 (DNA64897-1628).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 29 to about 311, inclusive of FIG. 84 (SEQ IDNO:140), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1412polypeptide having the sequence of amino acid residues from about 29 toabout 311, inclusive of FIG. 84 (SEQ ID NO:140), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1412 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 28 in the sequence of FIG.84 (SEQ ID NO:140). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 190 through aboutamino acid position 216 in the PRO1412 amino acid sequence (FIG. 84, SEQID NO:140).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 29to about 311, inclusive of FIG. 84 (SEQ ID NO:140), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1412 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1412polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1412 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 29 to 311 of FIG. 84 (SEQ ID NO:140).

In another aspect, the invention concerns an isolated PRO1412polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues29 to about 311, inclusive of FIG. 84 (SEQ ID NO:140).

In a further aspect, the invention concerns an isolated PRO1412polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 29 to311 of FIG. 84 (SEQ ID NO:140).

In yet another aspect, the invention concerns an isolated PRO1412polypeptide, comprising the sequence of amino acid residues 29 to about311, inclusive of FIG. 84 (SEQ ID NO:140), or a fragment thereofsufficient to provide a binding site for an anti-PRO1412 antibody.Preferably, the PRO1412 fragment retains a qualitative biologicalactivity of a native PRO1412 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1412 polypeptide having the sequence ofamino acid residues from about 29 to about 311, inclusive of FIG. 84(SEQ ID NO:140), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

43. PRO1557

A cDNA clone (DNA64902-1667) has been identified that encodes a novelpolypeptide having homology to chordin and designated in the presentapplication as “PRO1557”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1557 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1557 polypeptide having the sequence of amino acidresidues from 1 or about 26 to about 451, inclusive of FIG. 86 (SEQ IDNO:142), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1557 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 362 and about1639, inclusive, of FIG. 85 (SEQ ID NO:141). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203317(DNA64902-1667), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203317 (DNA64902-1667).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 26 to about 451, inclusive of FIG. 86 (SEQ IDNO:142), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1557polypeptide having the sequence of amino acid residues from about 26 toabout 451, inclusive of FIG. 86 (SEQ ID NO:142), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1557 polypeptide, with or withoutthe N-terminal signal sequence, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from amino acid position 1 through about aminoacid position 25 in the sequence of FIG. 86 (SEQ ID NO:142).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 26to about 451, inclusive of FIG. 86 (SEQ ID NO:142), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1557 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1557polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1557 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 26 to 451 of FIG. 86 (SEQ ID NO:142).

In another aspect, the invention concerns an isolated PRO1557polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues26 to about 451, inclusive of FIG. 86 (SEQ ID NO:142).

In a further aspect, the invention concerns an isolated PRO1557polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 26 to451 of FIG. 86 (SEQ ID NO:142).

In yet another aspect, the invention concerns an isolated PRO1557polypeptide, comprising the sequence of amino acid residues 26 to about451, inclusive of FIG. 86 (SEQ ID NO:142), or a fragment thereofsufficient to provide a binding site for an anti-PRO1557 antibody.Preferably, the PRO1557 fragment retains a qualitative biologicalactivity of a native PRO1557 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1557 polypeptide having the sequence ofamino acid residues from about 26 to about 451, inclusive of FIG. 86(SEQ ID NO:142), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1557 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1557 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1557 polypeptide by contactingthe native PRO1557 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1557 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

44. PRO1286

A cDNA clone (DNA64903-1553) has been identified that encodes a novelsecreted polypeptide that is designated in the present application as“PRO1286.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1286 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1286 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 93, inclusive of FIG. 88 (SEQ IDNO:144), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1286 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 147 and about371, inclusive, of FIG. 87 (SEQ ID NO:143). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203223(DNA64903-1553), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203223 (DNA64903-1553).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 93, inclusive of FIG. 88 (SEQ IDNO:144), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1286polypeptide having the sequence of amino acid residues from about 19 toabout 93, inclusive of FIG. 88 (SEQ ID NO:144), or (b) the complement ofthe DNA molecule of (a), and, if the DNA molecule has at least about an80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1286 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 18 in the sequence of FIG. 88 (SEQ IDNO:144).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 93, inclusive of FIG. 88 (SEQ ID NO:144), or (b) the complementof the DNA of (a).

Another embodiment is directed to fragments of a PRO1286 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1286polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1286 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 to 93 of FIG. 88 (SEQ ID NO:144).

In another aspect, the invention concerns an isolated PRO1286polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 93, inclusive of FIG. 88 (SEQ ID NO:144).

In a further aspect, the invention concerns an isolated PRO1286polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19 to93 of FIG. 88 (SEQ ID NO:144).

In yet another aspect, the invention concerns an isolated PRO1286polypeptide, comprising the sequence of amino acid residues 19 to about93, inclusive of FIG. 88 (SEQ ID NO:144), or a fragment thereofsufficient to provide a binding site for an anti-PRO1286 antibody.Preferably, the PRO1286 fragment retains a qualitative biologicalactivity of a native PRO1286 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1286 polypeptide having the sequence ofamino acid residues from about 19 to about 93, inclusive of FIG. 88 (SEQID NO:144), or (b) the complement of the DNA molecule of (a), and if thetest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

45. PRO1294

A cDNA clone (DNA64905-1558) has been identified, having homology tonucleic acid encoding olfactomedin, that encodes a novel polypeptide,designated in the present application as “PRO1294”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1294 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1294 polypeptide having the sequence of amino acidresidues from about 1 or about 22 to about 406, inclusive of FIG. 90(SEQ ID NO:146), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1294 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 110 orabout 173 and about 1327, inclusive, of FIG. 89 (SEQ ID NO:145).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203233(DNA64905-1558) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203233 (DNA64905-1558).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 22 to about 406, inclusive of FIG. 90 (SEQ IDNO:146), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1294 polypeptide having the sequence of amino acidresidues from 1 or about 22 to about 406, inclusive of FIG. 90 (SEQ IDNO:146), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1294 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 21 in the sequence of FIG. 90(SEQ ID NO:146).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 22 to about 406, inclusive of FIG. 90 (SEQ ID NO:146), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1294 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 89 (SEQ ID NO:145).

In another embodiment, the invention provides isolated PRO1294polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1294 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 22 to about 406 of FIG. 90(SEQ ID NO:146).

In another aspect, the invention concerns an isolated PRO1294polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 22 to about 406, inclusive of FIG. 90 (SEQ ID NO:146).

In a further aspect, the invention concerns an isolated PRO1294polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 22 to about 406, inclusive of FIG. 90 (SEQ ID NO:146).

In yet another aspect, the invention concerns an isolated PRO1294polypeptide, comprising the sequence of amino acid residues 1 or about22 to about 406, inclusive of FIG. 90 (SEQ ID NO:146), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1294antibody. Preferably, the PRO1294 fragment retains a qualitativebiological activity of a native PRO1294 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1294 polypeptide having the sequence ofamino acid residues from about 1 or about 22 to about 406, inclusive ofFIG. 90 (SEQ ID NO:146), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1294 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1294 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1294 polypeptide by contactingthe native PRO1294 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1294 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

46. PRO1347

A cDNA clone (DNA64950-1590) has been identified that encodes a novelpolypeptide having sequence identity with butyrophilin and designated inthe present application as “PRO1347.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1347 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1347 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 500, inclusive of FIG. 92 (SEQ IDNO:148), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1347 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 234 and about1682, inclusive, of FIG. 91 (SEQ ID NO:147). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203224(DNA64950-1590), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203224 (DNA64950-1590).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 18 to about 500, inclusive of FIG. 92 (SEQ IDNO:148), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1347polypeptide having the sequence of amino acid residues from about 18 toabout 500, inclusive of FIG. 92 (SEQ ID NO:148), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1347 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted (or that terminus truncated)or inactivated variants, or is complementary to such encoding nucleicacid molecule. The signal peptide has been tentatively identified asextending from amino acid position 1 through about amino acid position17 in the sequence of FIG. 92 (SEQ ID NO:148). The transmembrane domainhas been tentatively identified as extending from about amino acidposition 239 through about amino acid position 255 in the PRO1347 aminoacid sequence (FIG. 92, SEQ ID NO:148).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 18to about 500, inclusive of FIG. 92 (SEQ ID NO:148), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1347 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1347polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1347 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 18 through 500 of FIG. 92 (SEQ. ID NO:148).

In another aspect, the invention concerns an isolated PRO1347polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues18 to about 500, inclusive of FIG. 92 (SEQ ID NO:148).

In a further aspect, the invention concerns an isolated PRO1347polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 18through 500 of FIG. 92 (SEQ ID NO:148).

In yet another aspect, the invention concerns an isolated PRO1347polypeptide, comprising the sequence of amino acid residues 18 to about500, inclusive of FIG. 92 (SEQ ID NO:148), or a fragment thereofsufficient to provide a binding site for an anti-PRO1347 antibody.Preferably, the PRO1347 fragment retains a qualitative biologicalactivity of a native PRO1347 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1347 polypeptide having the sequence ofamino acid residues from about 18 to about 500, inclusive of FIG. 92(SEQ ID NO:148), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1347 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1347 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1347 polypeptide, by contactingthe native PRO1347 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1347 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

47. PRO1305

A cDNA clone (DNA64952-1568) has been identified that encodes a novelsecreted polypeptide, designated in the present application as“PRO1305”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1305 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1305 polypeptide having the sequence of amino acidresidues from about 1 or about 26 to about 258, inclusive of FIG. 94(SEQ ID NO:153), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1305 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 126 orabout 201 and about 899, inclusive, of FIG. 93 (SEQ ID NO:152).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203222(DNA64952-1568) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203222 (DNA64952-1568).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 26 to about 258, inclusive of FIG. 94 (SEQ IDNO:153), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1305 polypeptide having the sequence of amino acidresidues from 1 or about 26 to about 258, inclusive of FIG. 94 (SEQ IDNO:153), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1305 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 25 in the sequence of FIG. 94(SEQ ID NO:153).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 26 to about 258, inclusive of FIG. 94 (SEQ ID NO:153), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1305 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 93 (SEQ ID NO:152).

In another embodiment, the invention provides isolated PRO1305polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1305 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 26 to about 258 of FIG. 94(SEQ ID NO:153).

In another aspect, the invention concerns an isolated PRO1305polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 26 to about 258, inclusive of FIG. 94 (SEQ ID NO:153).

In a further aspect, the invention concerns an isolated PRO1305polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 26 to about 258, inclusive of FIG. 94 (SEQ ID NO:153).

In yet another aspect, the invention concerns an isolated PRO1305polypeptide, comprising the sequence of amino acid residues 1 or about26 to about 258, inclusive of FIG. 94 (SEQ ID NO:153), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1305antibody. Preferably, the PRO1305 fragment retains a qualitativebiological activity of a native PRO1305 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1305 polypeptide having the sequence ofamino acid residues from about 1 or about 26 to about 258, inclusive ofFIG. 94 (SEQ ID NO:153), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

48. PRO1273

A cDNA clone (DNA65402-1540) has been identified that encodes a novelpolypeptide having sequence identity with lipocalins and designated inthe present application as “PRO1273.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1273 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1273 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 163, inclusive of FIG. 96 (SEQ IDNO:158), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1273 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 86 and about514, inclusive, of FIG. 95 (SEQ ID NO:157). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203252(DNA65402-1540), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203252 (DNA65402-1540).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 21 to about 163, inclusive of FIG. 96 (SEQ IDNO:158), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1273polypeptide having the sequence of amino acid residues from about 21 toabout 163, inclusive of FIG. 96 (SEQ ID NO:158), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 21to about 163, inclusive of FIG. 96 (SEQ ID NO:158), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1273 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1273polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1273 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 21 through 163 of FIG. 96 (SEQ ID NO:158).

In another aspect, the invention concerns an isolated PRO1273polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues21 to about 163, inclusive of FIG. 96 (SEQ ID NO:158).

In a further aspect, the invention concerns an isolated PRO1273polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 21through 163 of FIG. 96 (SEQ ID NO:158).

In yet another aspect, the invention concerns an isolated PRO1273polypeptide, comprising the sequence of amino acid residues 21 to about163, inclusive of FIG. 96 (SEQ ID NO:158), or a fragment thereofsufficient to provide a binding site for an anti-PRO1273 antibody.Preferably, the PRO1273 fragment retains a qualitative biologicalactivity of a native PRO1273 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1273 polypeptide having the sequence ofamino acid residues from about 21 to about 163, inclusive of FIG. 96(SEQ ID NO:158), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1273 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1273 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1273 polypeptide, by contactingthe native PRO1273 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1273 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

49. PRO1302

A cDNA clone (DNA65403-1565) has been identified that encodes a novelpolypeptide having sequence identity with CD33 and designated in thepresent application as “PRO1302.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1302 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1302 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 463, inclusive of FIG. 98 (SEQ IDNO:160), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1302 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 88 and about1431, inclusive, of FIG. 97 (SEQ ID NO:159). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203230(DNA65403-1565), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203230 (DNA65403-1565).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 16 to about 463, inclusive of FIG. 98 (SEQ IDNO:160), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1302polypeptide having the sequence of amino acid residues from about 16 toabout 463, inclusive of FIG. 98 (SEQ ID NO:160), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1302 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted (or truncated form) orinactivated variants, or is complementary to such encoding nucleic acidmolecule. The signal peptide has been tentatively identified asextending from amino acid position 1 through about amino acid position15 in the sequence of FIG. 98 (SEQ ID NO:160). The transmembrane domainhas been tentatively identified as extending from about amino acidposition 351 through about amino acid position 370 in the PRO1302 aminoacid sequence (FIG. 98, SEQ ID NO:160).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 16to about 463, inclusive of FIG. 98 (SEQ ID NO:160), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1302 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1302polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1302 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 16 through 463 of FIG. 98 (SEQ ID NO:160).

In another aspect, the invention concerns an isolated PRO1302polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues16 to about 463, inclusive of FIG. 98 (SEQ ID NO:160).

In a further aspect, the invention concerns an isolated PRO1302polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 16through 463 of FIG. 98 (SEQ ID NO:160).

In yet another aspect, the invention concerns an isolated PRO1302polypeptide, comprising the sequence of amino acid residues 16 to about463, inclusive of FIG. 98 (SEQ ID NO:160), or a fragment thereofsufficient to provide a binding site for an anti-PRO1302 antibody.Preferably, the PRO1302 fragment retains a qualitative biologicalactivity of a native PRO1302 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1302 polypeptide having the sequence ofamino acid residues from about 16 to about 463, inclusive of FIG. 98(SEQ ID NO:160), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1302 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1302 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1302 polypeptide, by contactingthe native PRO1302 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1302 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

50. PRO1283

A cDNA clone (DNA65404-1551) has been identified, having homology tonucleic acid encoding odorant binding protein, that encodes a novelpolypeptide, designated in the present application as “PRO1283”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1283 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1283 polypeptide having the sequence of amino acidresidues from about 1 or about 18 to about 170, inclusive of FIG. 100(SEQ ID NO:162), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1283 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 45 or about96 and about 554, inclusive, of FIG. 99 (SEQ ID NO:161). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203244(DNA65404-1551) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203244 (DNA65404-1551).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 18 to about 170, inclusive of FIG. 100 (SEQ IDNO:162), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1283 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 170, inclusive of FIG. 100 (SEQ IDNO:162), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1283 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 17 in the sequence of FIG. 100(SEQ ID NO:162).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 18 to about 170, inclusive of FIG. 100 (SEQ ID NO:162), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1283 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 99 (SEQ ID NO:161).

In another embodiment, the invention provides isolated PRO1283polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1283 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 18 to about 170 of FIG. 100(SEQ ID NO:162).

In another aspect, the invention concerns an isolated PRO1283polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 18 to about 170, inclusive of FIG. 100 (SEQ ID NO:162).

In a further aspect, the invention concerns an isolated PRO1283polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 18 to about 170, inclusive of FIG. 100 (SEQ ID NO:162).

In yet another aspect, the invention concerns an isolated PRO1283polypeptide, comprising the sequence of amino acid residues 1 or about18 to about 170, inclusive of FIG. 100 (SEQ ID NO:162), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1283antibody. Preferably, the PRO1283 fragment retains a qualitativebiological activity of a native PRO1283 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1283 polypeptide having the sequence ofamino acid residues from about 1 or about 18 to about 170, inclusive ofFIG. 100 (SEQ ID NO:162), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1283 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1283 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1283 polypeptide by contactingthe native PRO1283 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1283 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

51. PRO1279

A cDNA clone (DNA65405-1547) has been identified, having homology tonucleic acid encoding neuropsin that encodes a novel polypeptide,designated in the present application as “PRO1279”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1279 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1279 polypeptide having the sequence of amino acidresidues from about 1 or about 19 to about 250, inclusive of FIG. 102(SEQ ID NO:170), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1279 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 106 orabout 160 and about 855, inclusive, of FIG. 101 (SEQ ID NO:169).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203476(DNA65405-1547) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203476 (DNA65405-1547).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 19 to about 250, inclusive of FIG. 102 (SEQ IDNO:170), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1279 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 250, inclusive of FIG. 102 (SEQ IDNO:170), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1279 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 18 in the sequence of FIG. 102(SEQ ID NO:170).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 19 to about 250, inclusive of FIG. 102 (SEQ ID NO:170), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1279 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 101 (SEQ ID NO:169).

In another embodiment, the invention provides isolated PRO1279polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1279 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 19 to about 250 of FIG. 102(SEQ ID NO:170).

In another aspect, the invention concerns an isolated PRO1279polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 19 to about 250, inclusive of FIG. 102 (SEQ ID NO:170).

In a further aspect, the invention concerns an isolated PRO1279polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 19 to about 250, inclusive of FIG. 102 (SEQ ID NO:170).

In yet another aspect, the invention concerns an isolated PRO1279polypeptide, comprising the sequence of amino acid residues 1 or about19 to about 250, inclusive of FIG. 102 (SEQ ID NO:170), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1279antibody. Preferably, the PRO1279 fragment retains a qualitativebiological activity of a native PRO1279 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1279 polypeptide having the sequence ofamino acid residues from about 1 or about 19 to about 250, inclusive ofFIG. 102 (SEQ ID NO:170), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1279 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1279 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1279 polypeptide by contactingthe native PRO1279 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1279 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

52. PRO1304

A cDNA clone (DNA65406-1567) has been identified, having homology tonucleic acid encoding FK506 binding protein that encodes a novelpolypeptide, designated in the present application as “PRO1304.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1304 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1304 polypeptide having the sequence of amino acidresidues from about 1 to about 222, inclusive of FIG. 104 (SEQ IDNO:180), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1304 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 23 andabout 688, inclusive, of FIG. 103 (SEQ ID NO:179). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203219(DNA65406-1567) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203219 (DNA65406-1567).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 to about 222, inclusive of FIG. 104 (SEQ ID NO:180), or(b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1304 polypeptide having the sequence of amino acidresidues from 1 to about 222, inclusive of FIG. 104 (SEQ ID NO:180), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1304 polypeptide, with or withoutthe initiating methionine, or is complementary to such encoding nucleicacid molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 222, inclusive of FIG. 104 (SEQ ID NO:180), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1304 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 103 (SEQ ID NO:179).

In another embodiment, the invention provides isolated PRO1304polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1304 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 to about 222 of FIG. 104 (SEQ IDNO:180).

In another aspect, the invention concerns an isolated PRO1304polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 222, inclusive of FIG. 104 (SEQ ID NO:180).

In a further aspect, the invention concerns an isolated PRO1304polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toabout 222, inclusive of FIG. 104 (SEQ ID NO:180).

In yet another aspect, the invention concerns an isolated PRO1304polypeptide, comprising the sequence of amino acid residues 1 to about222, inclusive of FIG. 104 (SEQ ID NO:180), or a fragment thereofsufficient to provide a binding site for an anti-PRO1304 antibody.Preferably, the PRO1304 fragment retains a qualitative biologicalactivity of a native PRO1304 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1304 polypeptide having the sequence ofamino acid residues from about 1 to about 222, inclusive of FIG. 104(SEQ ID NO:180), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1304 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1304 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1304 polypeptide by contactingthe native PRO1304 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1304 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

53. PRO1317

A cDNA clone (DNA65408-1578) has been identified that encodes a novelsecreted polypeptide that shares homology with human CD97. The novelpolypeptide is designated in the present application as “PRO1317”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1317 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1317 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 74, inclusive of FIG. 106 (SEQ IDNO:189), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1317 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 60 and about227, inclusive, of FIG. 105 (SEQ ID NO:188). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203217(DNA65408-1578), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203217 (DNA65408-1578).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 74, inclusive of FIG. 106 (SEQ IDNO:189), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1317polypeptide having the sequence of amino acid residues from about 19 toabout 74, inclusive of FIG. 106 (SEQ ID NO:189), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1317 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 18 in the sequence of FIG. 106 (SEQ IDNO:189).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 74, inclusive of FIG. 106 (SEQ ID NO:189), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1317 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1317polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1317 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 to 74 of FIG. 106 (SEQ ID NO:189).

In another aspect, the invention concerns an isolated PRO1317polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 74, inclusive of FIG. 106 (SEQ ID NO:189).

In a further aspect, the invention concerns an isolated PRO1317polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19 to74 of FIG. 106 (SEQ ID NO:189).

In yet another aspect, the invention concerns an isolated PRO1317polypeptide, comprising the sequence of amino acid residues 19 to about74, inclusive of FIG. 106 (SEQ ID NO:189), or a fragment thereofsufficient to provide a binding site for an anti-PRO1317 antibody.Preferably, the PRO1317 fragment retains a qualitative biologicalactivity of a native PRO1317 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1317 polypeptide having the sequence ofamino acid residues from about 19 to about 74, inclusive of FIG. 106(SEQ ID NO:189), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

54. PRO1303

A cDNA clone (DNA65409-1566) has been identified that encodes a novelpolypeptide having sequence identity with proteases including neuropsinand designated in the present application as “PRO1303.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1303 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1303 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 248, inclusive of FIG. 108 (SEQ IDNO:194), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1303 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 172 and about864, inclusive, of FIG. 107 (SEQ ID NO:193). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203232(DNA65409-1566), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203232 (DNA65409-1566).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 18 to about 248, inclusive of FIG. 108 (SEQ IDNO:194), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1303polypeptide having the sequence of amino acid residues from about 18 toabout 248, inclusive of FIG. 108 (SEQ ID NO:194), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 18to about 248, inclusive of FIG. 108 (SEQ ID NO:194), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1303 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1303polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1303 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 18 through 248 of FIG. 108 (SEQ ID NO:194).

In another aspect, the invention concerns an isolated PRO1303polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues18 to about 248, inclusive of FIG. 108 (SEQ ID NO:194).

In a further aspect, the invention concerns an isolated PRO1303polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 18through 248 of FIG. 108 (SEQ ID NO:194).

In yet another aspect, the invention concerns an isolated PRO1303polypeptide, comprising the sequence of amino acid residues 18 to about248, inclusive of FIG. 108 (SEQ ID NO:194), or a fragment thereofsufficient to provide a binding site for an anti-PRO1303 antibody.Preferably, the PRO1303 fragment retains a qualitative biologicalactivity of a native PRO1303 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1303 polypeptide having the sequence ofamino acid residues from about 18 to about 248, inclusive of FIG. 108(SEQ ID NO:194), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1303 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1303 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1303 polypeptide, by contactingthe native PRO1303 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1303 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

55. PRO1306

A cDNA clone (DNA65410-1569) has been identified that encodes a novelpolypeptide having homology to AIP1/daintain and designated in thepresent application as “PRO1306”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1306 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1306 polypeptide having the sequence of amino acidresidues from about 1 to about 150, inclusive of FIG. 110 (SEQ IDNO:196), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1306 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 106 and about555, inclusive, of FIG. 109 (SEQ ID NO:195). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203231(DNA65410-1569), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203231 (DNA65410-1569).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 150, inclusive of FIG. 110 (SEQ IDNO:196), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1306polypeptide having the sequence of amino acid residues from about 1 toabout 150, inclusive of FIG. 110 (SEQ ID NO:196), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 150, inclusive of FIG. 110 (SEQ ID NO:196), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1306 polypeptidecoding sequence that nay find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1306polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1306 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 150 of FIG. 110 (SEQ ID NO:196).

In another aspect, the invention concerns an isolated PRO1306polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 150, inclusive of FIG. 110 (SEQ ID NO:196).

In a further aspect, the invention concerns an isolated PRO1306polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toISO of FIG. 110 (SEQ ID NO:196).

In yet another aspect, the invention concerns an isolated PRO1306polypeptide, comprising the sequence of amino acid residues 1 to about150, inclusive of FIG. 110 (SEQ ID NO:196), or a fragment thereofsufficient to provide a binding site for an anti-PRO1306 antibody.Preferably, the PRO1306 fragment retains a qualitative biologicalactivity of a native PRO1306 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1306 polypeptide having the sequence ofamino acid residues from about 1 to about 150, inclusive of FIG. 110(SEQ ID NO:196), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1306 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1306 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1306 polypeptide, by contactingthe native PRO1306 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1306 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

56. PRO1336

A cDNA clone (DNA65423-1595) has been identified that encodes a novelpolypeptide having sequence identity with slit and designated in thepresent application as “PRO1336.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1336 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1336 polypeptide having the sequence of amino acidresidues from 1 or about 28 to about 1523, inclusive of FIG. 112 (SEQ IDNO:198), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1336 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 164 and about4651, inclusive, of FIGS. 111A-B (SEQ ID NO:197). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203227(DNA65423-1595), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203227 (DNA65423-1595).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 28 to about 1523, inclusive of FIG. 112 (SEQ IDNO:198), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1336polypeptide having the sequence of amino acid residues from about 28 toabout 1523, inclusive of FIG. 112 (SEQ ID NO:198), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 28to about 1523, inclusive of FIG. 112 (SEQ ID NO:198), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1336 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1336polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1336 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 28 through 1523 of FIG. 112 (SEQ IDNO:198).

In another aspect, the invention concerns an isolated PRO1336polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues28 to about 1523, inclusive of FIG. 112 (SEQ ID NO:198).

In a further aspect, the invention concerns an isolated PRO1336polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 28through 1523 of FIG. 112 (SEQ ID NO:198).

In yet another aspect, the invention concerns an isolated PRO1336polypeptide, comprising the sequence of amino acid residues 28 to about1523, inclusive of FIG. 112 (SEQ ID NO:198), or a fragment thereofsufficient to provide a binding site for an anti-PRO1336 antibody.Preferably, the PRO1336 fragment retains a qualitative biologicalactivity of a native PRO1336 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1336 polypeptide having the sequence ofamino acid residues from about 28 to about 1523, inclusive of FIG. 112(SEQ ID NO:198), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1336 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1336 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1336 polypeptide, by contactingthe native PRO1336 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1336 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

57. PRO1278

A cDNA clone (DNA66304-1546) has been identified that encodes a novelpolypeptide having homology to lysozyme C and designated in the presentapplication as “PRO1278.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1278 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1278 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 148, inclusive of FIG. 114 (SEQ IDNO:203), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1278 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 198 and about584, inclusive, of FIG. 113 (SEQ ID NO:202). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203321(DNA66304-1546), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203321 (DNA66304-1546).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 20 to about 148, inclusive of FIG. 114 (SEQ IDNO:203), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1278polypeptide having the sequence of amino acid residues from about 20 toabout 148, inclusive of FIG. 114 (SEQ ID NO:203), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1278 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 19 in the sequence of FIG.114 (SEQ ID NO:203).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 20to about 148, inclusive of FIG. 114 (SEQ ID NO:203), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1278 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1278polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1278 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 20 to 148 of FIG. 114 (SEQ ID NO:203).

In another aspect, the invention concerns an isolated PRO1278polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues20 to about 148, inclusive of FIG. 114 (SEQ ID NO:203).

In a further aspect, the invention concerns an isolated PRO1278polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 20 to148 of FIG. 114 (SEQ ID NO:203).

In yet another aspect, the invention concerns an isolated PRO1278polypeptide, comprising the sequence of amino acid residues 20 to about148, inclusive of FIG. 114 (SEQ ID NO:203), or a fragment thereofsufficient to provide a binding site for an anti-PRO1278 antibody.Preferably, the PRO1278 fragment retains a qualitative biologicalactivity of a native PRO1278 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1278 polypeptide having the sequence ofamino acid residues from about 20 to about 148, inclusive of FIG. 114(SEQ ID NO:203), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1278 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1278 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1278 polypeptide, by contactingthe native PRO1278 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1278 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

58. PRO1298

A cDNA clone (DNA66511-1563) has been identified that encodes a novelpolypeptide having sequence identity with glycosyltransferases anddesignated in the present application as “PRO1298.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1298 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1298 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 323, inclusive of FIG. 116 (SEQ IDNO:210), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1298 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 139 and about1062, inclusive, of FIG. 115 (SEQ ID NO:209). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203228(DNA66511-1563), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203228 (DNA66511-1563).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 16 to about 323, inclusive of FIG. 116 (SEQ IDNO:210), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1298polypeptide having the sequence of amino acid residues from about 16 toabout 323, inclusive of FIG. 116 (SEQ ID NO:210), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 16to about 323, inclusive of FIG. 116 (SEQ ID NO:210), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1298 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1298polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1298 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 16 through 323 of FIG. 116 (SEQ ID NO:210).

In another aspect, the invention concerns an isolated PRO1298polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues16 to about 323, inclusive of FIG. 116 (SEQ ID NO:210).

In a further aspect, the invention concerns an isolated PRO1298polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 16through 323 of FIG. 116 (SEQ ID NO:210).

In yet another aspect, the invention concerns an isolated PRO1298polypeptide, comprising the sequence of amino acid residues 16 to about323, inclusive of FIG. 116 (SEQ ID NO:210), or a fragment thereofsufficient to provide a binding site for an anti-PRO1298 antibody.Preferably, the PRO1298 fragment retains a qualitative biologicalactivity of a native PRO1298 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1298 polypeptide having the sequence ofamino acid residues from about 16 to about 323, inclusive of FIG. 116(SEQ ID NO:210), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1298 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1298 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1298 polypeptide, by contactingthe native PRO1298 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1298 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

59. PRO1301

A cDNA clone (DNA66512-1564) has been identified that encodes a novelpolypeptide having homology to cytochrome P450 and designated in thepresent application as “PRO1301.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1301 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1301 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 462, inclusive of FIG. 118 (SEQ IDNO:212), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1301 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 97 and about1428, inclusive, of FIG. 117 (SEQ ID NO:211). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203218(DNA66512-1564), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203218 (DNA66512-1564).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 462, inclusive of FIG. 118 (SEQ IDNO:212), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1301polypeptide having the sequence of amino acid residues from about 19 toabout 462, inclusive of FIG. 118 (SEQ ID NO:212), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1301 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 18 in the sequence of FIG.118 (SEQ ID NO:212). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 271 through aboutamino acid position 290 in the PRO1301 amino acid sequence (FIG. 118.SEQ ID NO:212).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 462, inclusive of FIG. 118 (SEQ ID NO:212), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1301 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1301polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1301 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 to 462 of FIG. 118 (SEQ ID NO:212).

In another aspect, the invention concerns an isolated PRO1301polypeptide, comprising an amino acid sequence having at least about 80%sequence identity preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 462, inclusive of FIG. 118 (SEQ ID NO:212).

In a further aspect, the invention concerns an isolated PRO1301polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19 to462 of FIG. 118 (SEQ ID NO:212).

In yet another aspect, the invention concerns an isolated PRO1301polypeptide, comprising the sequence of amino acid residues 19 to about462, inclusive of FIG. 118 (SEQ ID NO:212), or a fragment thereofsufficient to provide a binding site for an anti-PRO1301 antibody.Preferably, the PRO1301 fragment retains a qualitative biologicalactivity of a native PRO1301 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1301 polypeptide having the sequence ofamino acid residues from about 19 to about 462, inclusive of FIG. 118(SEQ ID NO:212), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

60. PRO1268

A cDNA clone (DNA66519-1535) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1268.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1268 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1268 polypeptide having the sequence of amino acidresidues from about 1 to about 140, inclusive of FIG. 120 (SEQ IDNO:214), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1268 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 89 and about508, inclusive, of FIG. 119 (SEQ ID NO:213). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203236(DNA66519-1535), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203236 (DNA66519-1535).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 140, inclusive of FIG. 120 (SEQ IDNO:214), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1268polypeptide having the sequence of amino acid residues from about 1 toabout 140, inclusive of FIG. 120 (SEQ ID NO:214), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1268 polypeptide, with one or moreof its soluble, i.e. transmembrane, domains deleted or inactivated, oris complementary to such encoding nucleic acid molecule. Transmembranedomains has been tentatively identified at about amino acids 12-28 (typeII), 51-66, and 107-124 in the PRO1268 amino acid sequence (FIG. 120,SEQ ID NO:214).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 140, inclusive of FIG. 120 (SEQ ID NO:214), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1268 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1268polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1268 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 140 of FIG. 120 (SEQ ID NO:214).

In another aspect, the invention concerns an isolated PRO1268polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 140, inclusive of FIG. 120 (SEQ ID NO:214).

In a further aspect, the invention concerns an isolated PRO1268polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to140 of FIG. 120 (SEQ ID NO:214).

In yet another aspect, the invention concerns an isolated PRO1268polypeptide, comprising the sequence of amino acid residues 1 to about140, inclusive of FIG. 120 (SEQ ID NO:214), or a fragment thereofsufficient to provide a binding site for an anti-PRO1268 antibody.Preferably, the PRO1268 fragment retains a qualitative biologicalactivity of a native PRO1268 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1268 polypeptide having the sequence ofamino acid residues from about 1 to about 140, inclusive of FIG. 120(SEQ ID NO:214), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

61. PRO1269

A cDNA clone (DNA66520-1536) has been identified that encodes a novelpolypeptide having homology to granulocyte peptide A and designated inthe present application as “PRO1269.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1269 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1269 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 196, inclusive of FIG. 122 (SEQ IDNO:216), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1269 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 86 and about613, inclusive, of FIG. 121 (SEQ ID NO:215). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203226(DNA66520-1536), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203226 (DNA66520-1536).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 21 to about 196, inclusive of FIG. 122 (SEQ IDNO:216), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1269polypeptide having the sequence of amino acid residues from about 21 toabout 196, inclusive of FIG. 122 (SEQ ID NO:216), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1269 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 20 in the sequence of FIG.122 (SEQ ID NO:216).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 21to about 196, inclusive of FIG. 122 (SEQ ID NO:21)6, or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1269 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1269polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1269 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 21 to 196 of FIG. 122 (SEQ ID NO:216).

In another aspect, the invention concerns an isolated PRO1269polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues21 to about 196, inclusive of FIG. 122 (SEQ ID NO:216).

In a further aspect, the invention concerns an isolated PRO1269polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 21 to196 of FIG. 122 (SEQ ID NO:216).

In yet another aspect, the invention concerns an isolated PRO1269polypeptide, comprising the sequence of amino acid residues 21 to about196, inclusive of FIG. 122 (SEQ ID NO:216), or a fragment thereofsufficient to provide a binding site for an anti-PRO1269 antibody.Preferably, the PRO1269 fragment retains a qualitative biologicalactivity of a native PRO1269 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1269 polypeptide having the sequence ofamino acid residues from about 21 to about 196, inclusive of FIG. 122(SEQ ID NO:216), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1269 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1269 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1269 polypeptide, by contactingthe native PRO1269 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1269 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

62. PRO1327

A cDNA clone (DNA66521-1583) has been identified, having homology tonucleic acid encoding neurexoplilin, that encodes a novel polypeptide,designated in the present application as “PRO1327”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1327 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1327 polypeptide having the sequence of amino acidresidues from about 1 or about 15 to about 252, inclusive of FIG. 124(SEQ ID NO:218), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1327 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 55 or about97 and about 810, inclusive, of FIG. 123 (SEQ ID NO:217). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203225(DNA66521-1583) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203225 (DNA66521-1583).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 15 to about 252, inclusive of FIG. 124 (SEQ IDNO:218), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 260 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1327 polypeptide having the sequence of amino acidresidues from 1 or about 15 to about 252, inclusive of FIG. 124 (SEQ IDNO:218), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1327 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 14 in the sequence of FIG. 124(SEQ ID NO:218).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 15 to about 252, inclusive of FIG. 124 (SEQ ID NO:218), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1327 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 123 (SEQ ID NO:217).

In another embodiment, the invention provides isolated PRO1327polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1327 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 15 to about 252 of FIG. 124(SEQ ID NO:218).

In another aspect, the invention concerns an isolated PRO1327polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 15 to about 252, inclusive of FIG. 124 (SEQ ID NO:218).

In a further aspect, the invention concerns an isolated PRO1327polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 15 to about 252, inclusive of FIG. 124 (SEQ ID NO:218).

In yet another aspect, the invention concerns an isolated PRO1327polypeptide, comprising the sequence of amino acid residues 1 or about15 to about 252, inclusive of FIG. 124 (SEQ ID NO:218), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1327antibody. Preferably, the PRO1327 fragment retains a qualitativebiological activity of a native PRO1327 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1327 polypeptide having the sequence ofamino acid residues from about 1 or about 15 to about 252, inclusive ofFIG. 124 (SEQ ID NO:218), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1327 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1327 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1327 polypeptide by contactingthe native PRO1327 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1327 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

63. PRO1382

A cDNA clone (DNA66526-1616) has been identified that encodes a novelpolypeptide having homology to cerebellin and designated in the presentapplication as “PRO1382.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1382 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1382 polypeptide having the sequence of amino acidresidues from 1 or about 28 to about 201, inclusive of FIG. 126 (SEQ IDNO:220), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1382 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 418 and about939, inclusive, of FIG. 125 (SEQ ID NO:219). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203246(DNA66526-1616), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203246 (DNA66526-1616).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 28 to about 201, inclusive of FIG. 126 (SEQ IDNO:220), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1382polypeptide having the sequence of amino acid residues from about 28 toabout 201, inclusive of FIG. 126 (SEQ ID NO:220), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1382 polypeptide, with or withoutthe N-terminal signal sequence, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from amino acid position 1 through about aminoacid position 27 in the sequence of FIG. 126 (SEQ ID NO:220).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 28to about 201, inclusive of FIG. 126 (SEQ ID NO:220), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1382 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments arc from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1382polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1382 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 28 to 201 of FIG. 126 (SEQ ID NO:220).

In another aspect, the invention concerns an isolated PRO1382polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues28 to about 201, inclusive of FIG. 126 (SEQ ID NO:220).

In a further aspect, the invention concerns an isolated PRO1382polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 28 to201 of FIG. 126 (SEQ ID NO:220).

In yet another aspect, the invention concerns an isolated PRO1382polypeptide, comprising the sequence of amino acid residues 28 to about201, inclusive of FIG. 126 (SEQ ID NO:220), or a fragment thereofsufficient to provide a binding site for an anti-PRO1382 antibody.Preferably, the PRO1382 fragment retains a qualitative biologicalactivity of a native PRO1382 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1382 polypeptide having the sequence ofamino acid residues from about 28 to about 201, inclusive of FIG. 126(SEQ ID NO:220), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1382 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1382 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1382 polypeptide, by contactingthe native PRO1382 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1382 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

64. PRO1328

A cDNA clone (DNA66658-1584) has been identified that encodes a noveltransmembrane polypeptide, designated in the present application as“PRO1328”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1328 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1328 polypeptide having the sequence of amino acidresidues from about 1 or about 20 to about 257, inclusive of FIG. 128(SEQ ID NO:225), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1328 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 9 or about66 and about 779, inclusive, of FIG. 127 (SEQ ID NO:224). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203229(DNA66658-1584) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203229 (DNA66658-1584).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 20 to about 257, inclusive of FIG. 128 (SEQ IDNO:225), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 475 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1328 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 257, inclusive of FIG. 128 (SEQ IDNO:225), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1328 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 19 in the sequence of FIG.128 (SEQ ID NO:225). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 32 to about aminoacid position 51, from about amino acid position 119 to about amino acidposition 138, from about amino acid position 152 to about amino acidposition 169 and from about amino acid position 216 to about amino acidposition 235 in the PRO1328 amino acid sequence (FIG. 128, SEQ IDNO:225).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 20 to about 257, inclusive of FIG. 128 (SEQ ID NO:225), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1328 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 127 (SEQ ID NO:224).

In another embodiment, the invention provides isolated PRO1328polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1328 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 20 to about 257 of FIG. 128(SEQ ID NO:225).

In another aspect, the invention concerns an isolated PRO1328polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 20 to about 257, inclusive of FIG. 128 (SEQ ID NO:225).

In a further aspect, the invention concerns an isolated PRO1328polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 20 to about 257, inclusive of FIG. 128 (SEQ ID NO:225).

In yet another aspect, the invention concerns an isolated PRO1328polypeptide, comprising the sequence of amino acid residues 1 or about20 to about 257, inclusive of FIG. 128 (SEQ ID NO:225), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1328antibody. Preferably, the PRO1328 fragment retains a qualitativebiological activity of a native PRO1328 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1328 polypeptide having the sequence ofamino acid residues from about 1 or about 20 to about 257, inclusive ofFIG. 128 (SEQ ID NO:225), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

65. PRO1325

A cDNA clone (DNA66659-1593) has been identified that encodes a noveltransmembrane polypeptide, designated in the present application as“PRO1325”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1325 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1325 polypeptide having the sequence of amino acidresidues from about 1 or about 19 to about 832, inclusive of FIG. 130(SEQ ID NO:227), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1325 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 51 or about105 and about 2546, inclusive, of FIG. 129 (SEQ ID NO:226). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203269(DNA66659-1593) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203269 (DNA66659-1593).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 19 to about 832, inclusive of FIG. 130 (SEQ IDNO:227), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1325 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 832, inclusive of FIG. 130 (SEQ IDNO:227), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1325 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 18 in the sequence of FIG.130 (SEQ ID NO:227). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 292 to aboutamino acid position 317, from about amino acid position 451 to aboutamino acid position 470, from about amino acid position 501 to aboutamino acid position 520, from about amino acid position 607 to aboutamino acid position 627 and from about amino acid position 751 to aboutamino acid position 770 in the PRO1325 amino acid sequence (FIG. 130,SEQ ID NO:227).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 19 to about 832, inclusive of FIG. 130 (SEQ ID NO:227), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1325 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 129 (SEQ ID NO:226).

In another embodiment, the invention provides isolated PRO1325polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1325 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 19 to about 832 of FIG. 130(SEQ ID NO:227).

In another aspect, the invention concerns an isolated PRO1325polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 19 to about 832, inclusive of FIG. 130 (SEQ ID NO:227).

In a further aspect, the invention concerns an isolated PRO1325polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 19 to about 832, inclusive of FIG. 130 (SEQ ID NO:227).

In yet another aspect, the invention concerns an isolated PRO1325polypeptide, comprising the sequence of amino acid residues 1 or about19 to about 832, inclusive of FIG. 130 (SEQ ID NO:227), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1325antibody. Preferably, the PRO1325 fragment retains a qualitativebiological activity of a native PRO1325 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule wider stringent conditions with(a) a DNA molecule encoding a PRO1325 polypeptide having the sequence ofamino acid residues from about 1 or about 19 to about 832, inclusive ofFIG. 130 (SEQ ID NO:227), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

66. PRO1340

A cDNA clone (DNA66663-1598) has been identified that encodes a novelpolypeptide having homology to Ksp-cadherin and designated in thepresent application as “PRO1340.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1340 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1340 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 807, inclusive of FIG. 132 (SEQ IDNO:229), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1340 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 182 and about2548, inclusive, of FIG. 131 (SEQ ID NO:228). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203268(DNA66663-1598), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203268 (DNA66663-1598).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 807, inclusive of FIG. 132 (SEQ IDNO:229), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1340polypeptide having the sequence of amino acid residues from about 19 toabout 807, inclusive of FIG. 132 (SEQ ID NO:229), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1340 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 18 in the sequence of FIG.132 (SEQ ID NO:229). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 762 to aboutamino acid position 784 in the PRO1340 amino acid sequence (FIG. 132,SEQ ID NO:229).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 807, inclusive of FIG. 132 (SEQ ID NO:229), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1340 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1340polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1340 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 to 807 of FIG. 132 (SEQ ID NO:229).

In another aspect, the invention concerns an isolated PRO1340polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 807, inclusive of FIG. 132 (SEQ ID NO:229).

In a further aspect, the invention concerns an isolated PRO1340polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19 to807 of FIG. 132 (SEQ ID NO:229).

In yet another aspect, the invention concerns an isolated PRO1340polypeptide, comprising the sequence of amino acid residues 19 to about807, inclusive of FIG. 132 (SEQ ID NO:229), or a fragment thereofsufficient to provide a binding site for an anti-PRO1340 antibody.Preferably, the PRO1340 fragment retains a qualitative biologicalactivity of a native PRO1340 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1340 polypeptide having the sequence ofamino acid residues from about 19 to about 807, inclusive of FIG. 132(SEQ ID NO:229), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1340 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1340 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1340 polypeptide, by contactingthe native PRO1340 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1340 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

67. PRO1339

A cDNA clone (DNA66669-1597) has been identified that encodes a novelpolypeptide having sequence identity with carboxypepsidases anddesignated in the present application as “PRO1339.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1339 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1339 polypeptide having the sequence of amino acidresidues from 1 or about 17 to about 421, inclusive of FIG. 134 (SEQ IDNO:234), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1339 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 58 and about1271, inclusive, of FIG. 133 (SEQ ID NO:233). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203272(DNA66669-1597), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203272 (DNA66669-1597).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 17 to about 421, inclusive of FIG. 134 (SEQ IDNO:234), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1339polypeptide having the sequence of amino acid residues from about 17 toabout 421, inclusive of FIG. 134 (SEQ ID NO:234), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 17to about 421, inclusive of FIG. 134 (SEQ ID NO:234), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1339 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments arc from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1339polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1339 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 17 through 421 of FIG. 134 (SEQ ID NO:234).

In another aspect, the invention concerns an isolated PRO1339polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues17 to about 421, inclusive of FIG. 134 (SEQ ID NO:234).

In a further aspect, the invention concerns an isolated PRO1339polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 17through 421 of FIG. 134 (SEQ ID NO:234).

In yet another aspect, the invention concerns an isolated PRO1339polypeptide, comprising the sequence of amino acid residues 17 to about421, inclusive of FIG. 134 (SEQ ID NO:234), or a fragment thereofsufficient to provide a binding site for an anti-PRO1339 antibody.Preferably, the PRO1339 fragment retains a qualitative biologicalactivity of a native PRO1339 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1339 polypeptide having the sequence ofamino acid residues from about 17 to about 421, inclusive of FIG. 134(SEQ ID NO:234), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1339 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1339 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1339 polypeptide, by contactingthe native PRO1339 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1339 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

68. PRO1337

A cDNA clone (DNA66672-1586) has been identified that encodes a novelpolypeptide having homology to human thyroxine-binding globulindesignated in the present application as “PRO1337”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1337 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1337 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 417, inclusive of FIG. 136 (SEQ IDNO:236), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1337 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 120 and about1310, inclusive, of FIG. 135 (SEQ ID NO:235). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203265(DNA66672-66672), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203265 (DNA66672-66672).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 21 to about 417, inclusive of FIG. 136 (SEQ IDNO:236), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1337polypeptide having the sequence of amino acid residues from about 21 toabout 417, inclusive of FIG. 136 (SEQ ID NO:236), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1337 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 20 in the sequence of FIG. 136 (SEQ IDNO:236).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 21to about 417, inclusive of FIG. 136 (SEQ ID NO:236), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1337 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments arc from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1337polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1337 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 21 to 417 of FIG. 136 (SEQ ID NO:236).

In another aspect, the invention concerns an isolated PRO1337polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues21 to about 417, inclusive of FIG. 136 (SEQ ID NO:236).

In a further aspect, the invention concerns an isolated PRO1337polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 21 to417 of FIG. 136 (SEQ ID NO:236).

In yet another aspect, the invention concerns an isolated PRO1337polypeptide, comprising the sequence of amino acid residues 21 to about417, inclusive of FIG. 136 (SEQ ID NO:236), or a fragment thereofsufficient to provide a binding site for an anti-PRO1337 antibody.Preferably, the PRO1337 fragment retains a qualitative biologicalactivity of a native PRO1337 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1337 polypeptide having the sequence ofamino acid residues from about 21 to about 417, inclusive of FIG. 136(SEQ ID NO:236), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1337 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1337 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1337 polypeptide, by contactingthe native PRO1337 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1337 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

69. PRO1342

A cDNA clone (DNA66674-1599) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1342”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1342 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1342 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 596, inclusive of FIG. 138 (SEQ IDNO:243), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1342 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 299 and about2026, inclusive, of FIG. 137 (SEQ ID NO:242). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203281(DNA66674-1599), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203281 (DNA66674-1599).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 21 to about 596, inclusive of FIG. 138 (SEQ IDNO:243), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1342polypeptide having the sequence of amino acid residues from about 21 toabout 596, inclusive of FIG. 138 (SEQ ID NO:243), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1342 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble variants (i.e. transmembrane domain deleted or inactivated), oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 20 in the sequence of FIG.138 (SEQ ID NO:243). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 510 to aboutamino acid position 532 in the PRO1342 amino acid sequence (FIG. 138,SEQ ID NO:243).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 21to about 596, inclusive of FIG. 138 (SEQ ID NO:243), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1342 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1342polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1342 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 21 to 596 of FIG. 138 (SEQ ID NO:243).

In another aspect, the invention concerns an isolated PRO1342polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues21 to about 596, inclusive of FIG. 138 (SEQ ID NO:243).

In a further aspect, the invention concerns an isolated PRO1342polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 21 to596 of FIG. 138 (SEQ ID NO:243).

In yet another aspect, the invention concerns an isolated PRO1342polypeptide, comprising the sequence of amino acid residues 21 to about596, inclusive of FIG. 138 (SEQ ID NO:243), or a fragment thereofsufficient to provide a binding site for an anti-PRO1342 antibody.Preferably, the PRO1342 fragment retains a qualitative biologicalactivity of a native PRO1342 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1342 polypeptide having the sequence ofamino acid residues from about 21 to about 596, inclusive of FIG. 138(SEQ ID NO:243), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

70. PRO1343

A cDNA clone (DNA66675-1587) has been identified that encodes a novelsecreted polypeptide, designated in the present application as“PRO1343”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1343 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1343 polypeptide having the sequence of amino acidresidues from about 1 or about 26 to about 247, inclusive of FIG. 140(SEQ ID NO:248), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1343 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 71 or about146 and about 811, inclusive, of FIG. 139 (SEQ ID NO:247). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203282(DNA66675-1587) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203282 (DNA66675-1587).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 26 to about 247, inclusive of FIG. 140 (SEQ IDNO:248), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1343 polypeptide having the sequence of amino acidresidues from 1 or about 26 to about 247, inclusive of FIG. 140 (SEQ IDNO:248), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1343 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 25 in the sequence of FIG. 140(SEQ ID NO:248).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 26 to about 247, inclusive of FIG. 140 (SEQ ID NO:248), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1343 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 46 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 139 (SEQ ID NO:247).

In another embodiment, the invention provides isolated PRO1343polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1343 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 26 to about 247 of FIG. 140(SEQ ID NO:248).

In another aspect, the invention concerns an isolated PRO1343polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 26 to about 247, inclusive of FIG. 140 (SEQ ID NO:248).

In a further aspect, the invention concerns an isolated PRO1343polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 26 to about 247, inclusive of FIG. 140 (SEQ ID NO:248).

In yet another aspect, the invention concerns an isolated PRO1343polypeptide, comprising the sequence of amino acid residues 1 or about26 to about 247, inclusive of FIG. 140 (SEQ ID NO:248), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1343antibody. Preferably, the PRO1343 fragment retains a qualitativebiological activity of a native PRO1343 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1343 polypeptide having the sequence ofamino acid residues from about 1 or about 26 to about 247, inclusive ofFIG. 140 (SEQ ID NO:248), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

71. PRO1480

A cDNA clone (DNA67962-1649) has been identified that encodes a novelpolypeptide having homology to Semaphorin C and designated in thepresent application as “PRO1480.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1480 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1480 polypeptide having the sequence of amino acidresidues from about 1 to about 837, inclusive of FIG. 142 (SEQ IDNO:253), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1480 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 241 and about2751, inclusive, of FIG. 141 (SEQ ID NO:252). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203291(DNA67962-1649), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203291 (DNA67962-1649).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 837, inclusive of FIG. 142 (SEQ IDNO:253), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1480polypeptide having the sequence of amino acid residues from about 1 toabout 837, inclusive of FIG. 142 (SEQ ID NO:253), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1480 polypeptide, its solublevariants, (i.e. transmembrane domains deleted or inactivated) or iscomplementary to such encoding nucleic acid molecule. Transmembranedomains have been tentatively identified as extending from about aminoacid position 23 to about amino acid position 46 (type II) and aboutamino acid position 718 to about amino acid position 738 in the PRO1480amino acid sequence (FIG. 142, SEQ ID NO:253).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 837, inclusive of FIG. 142 (SEQ ID NO:253), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1480 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1480polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1480 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 837 of FIG. 142 (SEQ ID NO:253).

In another aspect, the invention concerns an isolated PRO1480polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 837, inclusive of FIG. 142 (SEQ ID NO:253).

In a further aspect, the invention concerns an isolated PRO1480polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to837 of FIG. 142 (SEQ ID NO:253).

In yet another aspect, the invention concerns an isolated PRO1480polypeptide, comprising the sequence of amino acid residues 1 to about837, inclusive of FIG. 142 (SEQ ID NO:253), or a fragment thereofsufficient to provide a binding site for an anti-PRO1480 antibody.Preferably, the PRO1480 fragment retains a qualitative biologicalactivity of a native PRO1480 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1480 polypeptide having the sequence ofamino acid residues from about 1 to about 837, inclusive of FIG. 142(SEQ ID NO:253), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1480 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1480 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1480 polypeptide, by contactingthe native PRO1480 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1480 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

72. PRO1487

A cDNA clone (DNA68836-1656) has been identified that encodes a novelpolypeptide having homology to fringe protein and designated in thepresent application as “PRO1487”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1487 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1487 polypeptide having the sequence of amino acidresidues from 1 or about 24 to about 802, inclusive of FIG. 144 (SEQ IDNO:260), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1487 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 558 and about2894, inclusive, of FIGS. 143A-B (SEQ ID NO:259). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203455(DNA68836-1656), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203455 (DNA68836-1656).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 24 to about 802, inclusive of FIG. 144 (SEQ IDNO:260), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1487polypeptide having the sequence of amino acid residues from about 24 toabout 802, inclusive of FIG. 144 (SEQ ID NO:260), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1487 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 23 in the sequence of FIG. 144 (SEQ IDNO:260).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 24to about 802, inclusive of FIG. 144 (SEQ ID NO:260), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1487 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1487polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1487 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 24 to 802 of FIG. 144 (SEQ ID NO:260).

In another aspect, the invention concerns an isolated PRO1487polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues24 to about 802, inclusive of FIG. 144 (SEQ ID NO:260).

In a further aspect, the invention concerns an isolated PRO1487polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 24 to802 of FIG. 144 (SEQ ID NO:260).

In yet another aspect, the invention concerns an isolated PRO487polypeptide, comprising the sequence of amino acid residues 24 to about802, inclusive of FIG. 144 (SEQ ID NO:260), or a fragment thereofsufficient to provide a binding site for an anti-PRO1487 antibody.Preferably, the PRO1487 fragment retains a qualitative biologicalactivity of a native PRO1487 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1487 polypeptide having the sequence ofamino acid residues from about 24 to about 802, inclusive of FIG. 144(SEQ ID NO:260), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1487 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1487 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1487 polypeptide, by contactingthe native PRO1487 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1487 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

73. PRO1418

A cDNA clone (DNA68864-1629) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1418.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1418 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1418 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 350, inclusive of FIG. 146 (SEQ IDNO:265), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1418 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 195 and about1187, inclusive, of FIG. 145 (SEQ ID NO:264). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203276(DNA68864-1629), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203276 (DNA68864-1629).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 20 to about 350, inclusive of FIG. 146 (SEQ IDNO:265), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1418polypeptide having the sequence of amino acid residues from about 20 toabout 350, inclusive of FIG. 146 (SEQ ID NO:265), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 20to about 350, inclusive of FIG. 146 (SEQ ID NO:265), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1418 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1418polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1418 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 20 through 350 of FIG. 146 (SEQ ID NO:265).

In another aspect, the invention concerns an isolated PRO1418polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues20 to about 350, inclusive of FIG. 146 (SEQ ID NO:265).

In a further aspect, the invention concerns an isolated PRO1418polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 20through 350 of FIG. 146 (SEQ ID NO:265).

In yet another aspect, the invention concerns an isolated PRO1418polypeptide, comprising the sequence of amino acid residues 20 to about350, inclusive of FIG. 146 (SEQ ID NO:265), or a fragment thereofsufficient to provide a binding site for an anti-PRO1418 antibody.Preferably, the PRO1418 fragment retains a qualitative biologicalactivity of a native PRO1418 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1418 polypeptide having the sequence ofamino acid residues from about 20 to about 350, inclusive of FIG. 146(SEQ ID NO:265), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1418 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1418 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1418 polypeptide, by contactingthe native PRO1418 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1418 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

74. PRO1472

A cDNA clone (DNA68866-1644) has been identified that encodes a novelpolypeptide having sequence identity with butyrophilin and designated inthe present application as “PRO1472.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1472 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1472 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 466, inclusive of FIG. 148 (SEQ IDNO:267), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1472 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 185 and about1531, inclusive, of FIG. 147 (SEQ ID NO:266). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203283(DNA68866-1644), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203283 (DNA68866-1644).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 18 to about 466, inclusive of FIG. 148 (SEQ IDNO:267), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1472polypeptide having the sequence of amino acid residues from about 18 toabout 466, inclusive of FIG. 148 (SEQ ID NO:267), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1472 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domains deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 1-17 in the sequence ofFIG. 148 (SEQ ID NO:267). The transmembrane domains have beententatively identified as being from about amino acid position 131through about amino acid position 150 and from about amino acid position235 through about amino acid position 259 in the PRO1472 amino acidsequence (FIG. 148, SEQ ID NO:267). It is understood that PRO1472 can bemanipulated to contain only particular regions given the informationherein, e.g. to have only the extracellular or cytoplasmic regions only,or to have the carboxyl end truncated wherein the second transmembranedomain is deleted.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 18to about 466, inclusive of FIG. 148 (SEQ ID NO:267), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1472 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1472polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1472 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 18 through 466 of FIG. 148 (SEQ ID NO:267).

In another aspect, the invention concerns an isolated PRO1472polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues18 to about 466, inclusive of FIG. 148 (SEQ ID NO:267).

In a further aspect, the invention concerns an isolated PRO1472polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 18through 466 of FIG. 148 (SEQ ID NO:267).

In yet another aspect, the invention concerns an isolated PRO1472polypeptide, comprising the sequence of amino acid residues 18 to about466, inclusive of FIG. 148 (SEQ ID NO:267), or a fragment thereofsufficient to provide a binding site for an anti-PRO1472 antibody.Preferably, the PRO1472 fragment retains a qualitative biologicalactivity of a native PRO1472 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1472 polypeptide having the sequence ofamino acid residues from about 18 to about 466, inclusive of FIG. 148(SEQ ID NO:267), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1472 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1472 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1472 polypeptide, by contactingthe native PRO1472 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1472 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

75. PRO1461

A cDNA clone (DNA68871-1638) has been identified that encodes a novelpolypeptide having homology to serine protease and designated in thepresent application as “PRO1461”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1461 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1461 polypeptide having the sequence of amino acidresidues from about 1 to about 423, inclusive of FIG. 150 (SEQ IDNO:269), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1461 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 32 and about1300, inclusive, of FIG. 149 (SEQ ID NO:268). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203280(DNA68871-68871), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203280 (DNA68871-68871).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 423, inclusive of FIG. 150 (SEQ IDNO:269), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1461polypeptide having the sequence of amino acid residues from about 1 toabout 423, inclusive of FIG. 150 (SEQ ID NO:269), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1461 polypeptide, with or withoutthe initiating methionine, and its soluble variants (i.e. transmembranedomain deleted or inactivated), or is complementary to such encodingnucleic acid molecule. A type II transmembrane domain has beententatively identified as extending from about amino acid position 21 toabout amino acid position 40 in the PRO1461 amino acid sequence (FIG.150, SEQ ID NO:269).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 423, inclusive of FIG. 150 (SEQ ID NO:269), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1461 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1461polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1461 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 423 of FIG. 150 (SEQ ID NO:269).

In another aspect, the invention concerns an isolated PRO1461polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 423, inclusive of FIG. 150 (SEQ ID NO:269).

In a further aspect, the invention concerns an isolated PRO1461polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to423 of FIG. 150 (SEQ ID NO:269).

In yet another aspect, the invention concerns an isolated PRO1461polypeptide, comprising the sequence of amino acid residues 1 to about423, inclusive of FIG. 150 (SEQ ID NO:269), or a fragment thereofsufficient to provide a binding site for an anti-PRO1461 antibody.Preferably, the PRO1461 fragment retains a qualitative biologicalactivity of a native PRO1461 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1461 polypeptide having the sequence ofamino acid residues from about 1 to about 423, inclusive of FIG. 150(SEQ ID NO:269), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1461 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1461 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1461 polypeptide, by contactingthe native PRO1461 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1461 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

76. PRO1410

A cDNA clone (DNA68874-1622) has been identified that encodes a noveltransmembrane polypeptide, designated in the present application as“PRO1410”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1410 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1410 polypeptide having the sequence of amino acidresidues from about 1 or about 21 to about 238, inclusive of FIG. 152(SEQ ID NO:271), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1410 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 152 orabout 212 and about 865, inclusive, of FIG. 151 (SEQ ID NO:270).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203277(DNA68874-1622) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203277 (DNA68874-1622).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 21 to about 238, inclusive of FIG. 152 (SEQ IDNO:271), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1410 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 238, inclusive of FIG. 152 (SEQ IDNO:271), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1410 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 20 in the sequence of FIG.152 (SEQ ID NO:271). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 194 to aboutamino acid position 220 in the PRO1410 amino acid sequence (FIG. 152,SEQ ID NO:271).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 21 to about 238, inclusive of FIG. 152 (SEQ ID NO:271), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1410 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 151 (SEQ ID NO:270).

In another embodiment, the invention provides isolated PRO1410polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1410 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 21 to about 238 of FIG. 152(SEQ ID NO:271).

In another aspect, the invention concerns an isolated PRO1410polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 21 to about 238, inclusive of FIG. 152 (SEQ ID NO:271).

In a further aspect, the invention concerns an isolated PRO1410polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 21 to about 238, inclusive of FIG. 152 (SEQ ID NO:271).

In yet another aspect, the invention concerns an isolated PRO1410polypeptide, comprising the sequence of amino acid residues 1 or about21 to about 238, inclusive of FIG. 152 (SEQ ID NO:271), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1410antibody. Preferably, the PRO1410 fragment retains a qualitativebiological activity of a native PRO1410 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1410 polypeptide having the sequence ofamino acid residues from about 1 or about 21 to about 238, inclusive ofFIG. 152 (SEQ ID NO:271), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1410 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1410 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1410 polypeptide by contactingthe native PRO1410 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1410 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

77. PRO1568

A cDNA clone (DNA68880-1676) has been identified that encodes a novelpolypeptide having sequence identity with tetraspanins and designated inthe present application as “PRO1568.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1568 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1568 polypeptide having the sequence of amino acidresidues from 1 or about 34 to about 305, inclusive of FIG. 154 (SEQ IDNO:273), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1568 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 307 and about1122, inclusive, of FIG. 153 (SEQ ID NO:272). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203319(DNA68880-1676), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203319 (DNA68880-1676).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 34 to about 305, inclusive of FIG. 154 (SEQ IDNO:273), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1568polypeptide having the sequence of amino acid residues from about 34 toabout 305, inclusive of FIG. 154 (SEQ ID NO:273), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1568 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 33 in the sequence of FIG.154 (SEQ ID NO:273). The transmembrane domains have been tentativelyidentified as extending from about amino acids 12-35, 57-86, 94-114 and226-248 in the PRO1568 amino acid sequence (FIG. 154, SEQ ID NO:273).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 34to about 305, inclusive of FIG. 154 (SEQ ID NO:273), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1568 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1568polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1568 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 34 through 305 of FIG. 154 (SEQ ID NO:273).

In another aspect, the invention concerns an isolated PRO1568polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues34 to about 305, inclusive of FIG. 154 (SEQ ID NO:273).

In a further aspect, the invention concerns an isolated PRO1568polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 34through 305 of FIG. 154 (SEQ ID NO:273).

In yet another aspect, the invention concerns an isolated PRO1568polypeptide, comprising the sequence of amino acid residues 34 to about305, inclusive of FIG. 154 (SEQ ID NO:273), or a fragment thereofsufficient to provide a binding site for an anti-PRO1568 antibody.Preferably, the PRO1568 fragment retains a qualitative biologicalactivity of a native PRO1568 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1568 polypeptide having the sequence ofamino acid residues from about 34 to about 305, inclusive of FIG. 154(SEQ ID NO:273), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1568 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1568 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1568 polypeptide, by contactingthe native PRO1568 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1568 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

78. PRO1570

A cDNA clone (DNA68885-1678) has been identified that encodes a novelpolypeptide having sequence identity with SP60 and designated in thepresent application as “PRO1570.” In particular, for the first time,Applicants have identified an additional 199 amino acids on the aminoterminal end of the protein previously identified as SP60.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1570 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1570 polypeptide having the sequence of amino acidresidues from about 1 to about 432, inclusive of FIG. 156 (SEQ IDNO:275), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1570 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 210 and about1505, inclusive, of FIG. 155 (SEQ ID NO:274). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203311(DNA68885-1678), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203311 (DNA68885-1678).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 432, inclusive of FIG. 156 (SEQ IDNO:275), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1570polypeptide having the sequence of amino acid residues from about 1 toabout 432, inclusive of FIG. 156 (SEQ ID NO:275), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule. In a preferred embodiment, the probesprovided herein are from the amino terminal end of the peptideidentified in FIG. 1, defined as amino acids 1-199 of SEQ ID NO:275.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1570 polypeptide, in a form whichis secreted and is soluble, i.e. transmembrane domain deleted, truncatedor inactivated variants.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 432, inclusive of FIG. 156 (SEQ ID NO:275), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1570 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length. Preferably,the probes are from the amino terminal end as provided herein.

In another embodiment, the invention provides isolated PRO1570polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1570 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 through 432 of FIG. 156 (SEQ ID NO:275).

In another aspect, the invention concerns an isolated PRO1570polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 432, inclusive of FIG. 156 (SEQ ID NO:275).

In a further aspect, the invention concerns an isolated PRO1570polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1through 432 of FIG. 156 (SEQ ID NO:275).

In yet another aspect, the invention concerns an isolated PRO1570polypeptide, comprising the sequence of amino acid residues 1 to about432, inclusive of FIG. 156 (SEQ ID NO:275), or a fragment thereofsufficient to provide a binding site for an anti-PRO1570 antibody.Preferably, the PRO1570 fragment retains a qualitative biologicalactivity of a native PRO1570 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1570 polypeptide having the sequence ofamino acid residues from about 1 to about 432, inclusive of FIG. 156(SEQ ID NO:275), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1570 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1570 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1570 polypeptide, by contactingthe native PRO1570 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1570 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

79. PRO1317

A cDNA clone (DNA71166-1685) has been identified that encodes a novelpolypeptide having homology to semaphorin B and designated in thepresent application as “PRO1317”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1317 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1317 polypeptide having the sequence of amino acidresidues from 1 or about 31 to about 761, inclusive of FIG. 158 (SEQ IDNO:277), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1317 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 195 and about2387, inclusive, of FIG. 157 (SEQ ID NO:276). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203355(DNA71166-1685), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203355 (DNA71166-1685).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 31 to about 761, inclusive of FIG. 158 (SEQ IDNO:277), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1317polypeptide having the sequence of amino acid residues from about 31 toabout 761, inclusive of FIG. 158 (SEQ ID NO:277), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1317 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble variants (i.e. transmembrane domains deleted or inactivated), oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 30 in the sequence of FIG.158 (SEQ ID NO:277). Transmembrane domains have been tentativelyidentified as extending from about amino acid positions 13-31, 136-156,222-247, 474-490, and 685-704 in the PRO1317 amino acid sequence (FIG.158, SEQ ID NO:277).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 31to about 761, inclusive of FIG. 158 (SEQ ID NO:277), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1317 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1317polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1317 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 31 to 761 of FIG. 158 (SEQ ID NO:277).

In another aspect, the invention concerns an isolated PRO1317polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues31 to about 761, inclusive of FIG. 158 (SEQ ID NO:277).

In a further aspect, the invention concerns an isolated PRO1317polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 31 to761 of FIG. 158 (SEQ ID NO:277).

In yet another aspect, the invention concerns an isolated PRO1317polypeptide, comprising the sequence of amino acid residues 31 to about761, inclusive of FIG. 158 (SEQ ID NO:277), or a fragment thereofsufficient to provide a binding site for an anti-PRO1317 antibody.Preferably, the PRO1317 fragment retains a qualitative biologicalactivity of a native PRO1317 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1317 polypeptide having the sequence ofamino acid residues from about 31 to about 761, inclusive of FIG. 158(SEQ ID NO:277), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1317 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1317 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1317 polypeptide, by contactingthe native PRO1317 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1317 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

80. PRO1780

A cDNA clone (DNA71169-1709) has been identified that encodes a novelpolypeptide having homology to glucuronosyltransferase and designated inthe present application as “PRO1780”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1780 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1780 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 523, inclusive of FIG. 160 (SEQ IDNO:282), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1780 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 125 and about1636, inclusive, of FIG. 159 (SEQ ID NO:281). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203467(DNA71169-1709), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203467 (DNA71169-1709).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 20 to about 523, inclusive of FIG. 160 (SEQ IDNO:282), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 and produced by hybridizing a test DNA molecule understringent conditions with (a) a DNA molecule encoding a PRO1780polypeptide having the sequence of amino acid residues from about 20 toabout 523, inclusive of FIG. 160 (SEQ ID NO:282), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1780 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble variants (i.e. transmembrane domain deleted or inactivated), oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 19 in the sequence of FIG.160 (SEQ ID NO:282). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 483 to aboutamino acid position 504 in the PRO1780 amino acid sequence (FIG. 160,SEQ ID NO:282).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 20to about 523, inclusive of FIG. 160 (SEQ ID NO:282), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1780 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1780polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1780 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 20 to 523 of FIG. 160 (SEQ ID NO:282).

In another aspect, the invention concerns an isolated PRO1780polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues20 to about 523, inclusive of FIG. 160 (SEQ ID NO:282).

In a further aspect, the invention concerns an isolated PRO1780polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 20 to523 of FIG. 160 (SEQ ID NO:282).

In yet another aspect, the invention concerns an isolated PRO1780polypeptide, comprising the sequence of amino acid residues 20 to about523, inclusive of FIG. 160 (SEQ ID NO:282), or a fragment thereofsufficient to provide a binding site for an anti-PRO1780 antibody.Preferably, the PRO1780 fragment retains a qualitative biologicalactivity of a native PRO1780 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1780 polypeptide having the sequence ofamino acid residues from about 20 to about 523, inclusive of FIG. 160(SEQ ID NO:282), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1780 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1780 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1780 polypeptide, by contactingthe native PRO1780 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1780 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

81. PRO1486

A cDNA clone (DNA71180-1655) has been identified that encodes a novelpolypeptide having sequence identity with cerebellin, particularlyprecerebellin, and designated in the present application as “PRO1486.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1486 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1486 polypeptide having the sequence of amino acidresidues from 1 or about 33 to about 205, inclusive of FIG. 162 (SEQ IDNO:287), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1486 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 568 and about1086, inclusive, of FIG. 161 (SEQ ID NO:286). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203403(DNA71180-1655), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203403 (DNA71180-1655).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 33 to about 205, inclusive of FIG. 162 (SEQ IDNO:287), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1486polypeptide having the sequence of amino acid residues from about 33 toabout 205, inclusive of FIG. 162 (SEQ ID NO:287), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 33to about 205, inclusive of FIG. 162 (SEQ ID NO:287), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1486 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1486polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1486 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 33 through 205 of FIG. 162 (SEQ ID NO:287).

In another aspect, the invention concerns an isolated PRO1486polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues33 to about 205, inclusive of FIG. 162 (SEQ ID NO:287).

In a further aspect, the invention concerns an isolated PRO1486polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 33through 205 of FIG. 162 (SEQ ID NO:287).

In yet another aspect, the invention concerns an isolated PRO1486polypeptide, comprising the sequence of amino acid residues 33 to about205, inclusive of FIG. 162 (SEQ ID NO:287), or a fragment thereofsufficient to provide a binding site for an anti-PRO1486 antibody.Preferably, the PRO1486 fragment retains a qualitative biologicalactivity of a native PRO1486 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1486 polypeptide having the sequence ofamino acid residues from about 33 to about 205, inclusive of FIG. 162(SEQ ID NO:287), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1486 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1486 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1486 polypeptide, by contactingthe native PRO1486 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1486 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

82. PRO1433

A cDNA clone (DNA71184-1634) has been identified that encodes a noveltransmembrane polypeptide, designated in the present application as“PRO1433”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1433 polypeptide.

In one aspect, the isolated nucleic acid, comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1433 polypeptide having the sequence of amino acidresidues from about 1 to about 388, inclusive of FIG. 164 (SEQ IDNO:292), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1433 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 185 andabout 1348, inclusive, of FIG. 163 (SEQ ID NO:291). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203266(DNA71184-1634) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203266 (DNA71184-1634).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 to about 388; inclusive of FIG. 164 (SEQ ID NO:292), or(b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 250 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1433 polypeptide having the sequence of amino acidresidues from 1 to about 388, inclusive of FIG. 164 (SEQ ID NO:292), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1433 polypeptide, with or withoutthe initiating methionine, and its soluble, i.e., transmembrane domaindeleted or inactivated variants, or is complementary to such encodingnucleic acid molecule. The transmembrane domain has been tentativelyidentified as extending from about amino acid position 76 to about aminoacid position 97 in the PRO1433 amino acid sequence (FIG. 164, SEQ IDNO:292).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 388, inclusive of FIG. 164 (SEQ ID NO:292), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1433 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 163 (SEQ ID NO:291).

In another embodiment, the invention provides isolated PRO1433polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1433 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 to about 388 of FIG. 164 (SEQ IDNO:292).

In another aspect, the invention concerns an isolated PRO1433polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 388, inclusive of FIG. 164 (SEQ ID NO:292).

In a further aspect, the invention concerns an isolated PRO1433polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toabout 388, inclusive of FIG. 164 (SEQ ID NO:292).

In yet another aspect, the invention concerns an isolated PRO1433polypeptide, comprising the sequence of amino acid residues 1 to about388, inclusive of FIG. 164 (SEQ ID NO:292), or a fragment thereofsufficient to provide a binding site for an anti-PRO1433 antibody.Preferably, the PRO1433 fragment retains a qualitative biologicalactivity of a native PRO1433 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1433 polypeptide having the sequence ofamino acid residues from about 1 to about 388, inclusive of FIG. 164(SEQ ID NO:292), or (b) the complement of the DNA molecule of (a), andif the lest DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1433 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1433 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1433 polypeptide by contactingthe native PRO1433 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1433 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

83. PRO1490

A cDNA clone (DNA71213-1659) has been identified, having homology tonucleic acid encoding a 1-acyl-sn-glycerol-3-phosphate acyltransferaseprotein that encodes a novel polypeptide, designated in the presentapplication as “PRO1490”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1490 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1490 polypeptide having the sequence of amino acidresidues from about 1 or about 26 to about 368, inclusive of FIG. 166(SEQ ID NO:297), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1490 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 272 orabout 347 and about 1375, inclusive, of FIG. 165 (SEQ ID NO:296).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203401(DNA71213-1659) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203401 (DNA71213-1659).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 26 to about 368, inclusive of FIG. 166 (SEQ IDNO:297), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 285 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1490 polypeptide having the sequence of amino acidresidues from 1 or about 26 to about 368, inclusive of FIG. 166 (SEQ IDNO:297), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1490 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 25 in the sequence of FIG.166 (SEQ ID NO:297). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 307 to aboutamino acid position 323 and from about amino acid position 335 to aboutamino acid position 352 in the PRO1490 amino acid sequence (FIG. 166,SEQ ID NO:297).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 26 to about 368, inclusive of FIG. 166 (SEQ ID NO:297), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1490 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 165 (SEQ ID NO:296).

In another embodiment, the invention provides isolated PRO1490polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1490 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 26 to about 368 of FIG. 166(SEQ ID NO:297).

In another aspect, the invention concerns an isolated PRO1490polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 26 to about 368, inclusive of FIG. 166 (SEQ ID NO:297).

In a further aspect, the invention concerns an isolated PRO1490polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 26 to about 368, inclusive of FIG. 166 (SEQ ID NO:297).

In yet another aspect, the invention concerns an isolated PRO1490polypeptide, comprising the sequence of amino acid residues 1 or about26 to about 368, inclusive of FIG. 166 (SEQ ID NO:297), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1490antibody. Preferably, the PRO1490 fragment retains a qualitativebiological activity of a native PRO1490 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1490 polypeptide having the sequence ofamino acid residues from about 1 or about 26 to about 368, inclusive ofFIG. 166 (SEQ ID NO:297), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1490 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1490 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1490 polypeptide by contactingthe native PRO1490 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1490 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

84. PRO1482

A cDNA clone (DNA71234-1651) has been identified that encodes a novelsecreted polypeptide, designated in the present application as“PRO1482”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1482 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1482 polypeptide having the sequence of amino acidresidues from about 1 or about 29 to about 143, inclusive of FIG. 168(SEQ ID NO:302), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1482 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 33 or about117 and about 461, inclusive, of FIG. 167 (SEQ ID NO:301). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203402(DNA71234-1651) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203402 (DNA71234-1651).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 29 to about 143, inclusive of FIG. 168 (SEQ IDNO:302), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 260 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1482 polypeptide having the sequence of amino acidresidues from 1 or about 29 to about 143, inclusive of FIG. 168 (SEQ IDNO:302), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1482 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 28 in the sequence of FIG. 168(SEQ ID NO:302).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 29 to about 143, inclusive of FIG. 168 (SEQ ID NO:302), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1482 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 167 (SEQ ID NO:301).

In another embodiment, the invention provides isolated PRO1482polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1482 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 29 to about 143 of FIG. 168(SEQ ID NO:302).

In another aspect, the invention concerns an isolated PRO1482polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 29 to about 143, inclusive of FIG. 168 (SEQ ID NO:302).

In a further aspect, the invention concerns an isolated PRO1482polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 29 to about 143, inclusive of FIG. 168 (SEQ ID NO:302).

In yet another aspect, the invention concerns an isolated PRO1482polypeptide, comprising the sequence of amino acid residues 1 or about29 to about 143, inclusive of FIG. 168 (SEQ ID NO:302), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1482antibody. Preferably, the PRO1482 fragment retains a qualitativebiological activity of a native PRO1482 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1482 polypeptide having the sequence ofamino acid residues from about 1 or about 29 to about 143, inclusive ofFIG. 168 (SEQ ID NO:302), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1482 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1482 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1482 polypeptide by contactingthe native PRO1482 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1482 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

85. PRO1446

A cDNA clone (DNA71277-1636) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1446.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1446 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1446 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 109, inclusive of FIG. 170 (SEQ IDNO:304), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1446 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 197 and about478, inclusive, of FIG. 169 (SEQ ID NO:303). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203285(DNA71277-1636), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203285 (DNA71277-1636).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 16 to about 109, inclusive of FIG. 170 (SEQ IDNO:304), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1446polypeptide having the sequence of amino acid residues from about 16 toabout 109, inclusive of FIG. 170 (SEQ ID NO:304), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 16to about 109, inclusive of FIG. 170 (SEQ ID NO: 304), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1446 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1446polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1446 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 16 through 109 of FIG. 170 (SEQ ID NO:304).

In another aspect, the invention concerns an isolated PRO1446polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues16 to about 109, inclusive of FIG. 170 (SEQ ID NO:304).

In a further aspect, the invention concerns an isolated PRO1446polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 16through 109 of FIG. 170 (SEQ ID NO:304).

In yet another aspect, the invention concerns an isolated PRO1446polypeptide, comprising the sequence of amino acid residues 16 to about109, inclusive of FIG. 170 (SEQ ID NO:304), or a fragment thereofsufficient to provide a binding site for an anti-PRO1446 antibody.Preferably, the PRO1446 fragment retains a qualitative biologicalactivity of a native PRO1446 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1446 polypeptide having the sequence ofamino acid residues from about 16 to about 109, inclusive of FIG. 170(SEQ ID NO:304), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1446 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1446 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1446 polypeptide, by contactingthe native PRO1446 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1446 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

86. PRO1558

A cDNA clone (DNA71282-1668) has been identified, having homology tonucleic acid encoding methyltransferase enzymes that encodes a novelpolypeptide, designated in the present application as “PRO1558”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1558 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1558 polypeptide having the sequence of amino acidresidues from about 1 or about 26 to about 262, inclusive of FIG. 172(SEQ ID NO:306), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1558 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 84 or about159 and about 869, inclusive, of FIG. 171 (SEQ ID NO:305). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203312(DNA71282-1668) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203312 (DNA71282-1668).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 26 to about 262, inclusive of FIG. 172 (SEQ IDNO:306), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1558 polypeptide having the sequence of amino acidresidues from 1 or about 26 to about 262, inclusive of FIG. 172 (SEQ IDNO:306), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1558 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 25 in the sequence of FIG.172 (SEQ ID NO:306). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 8 to about aminoacid position 30 and from about amino acid position 109 to about aminoacid position 130 in the PRO1558 amino acid sequence (FIG. 172, SEQ IDNO:306).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 26 to about 262, inclusive of FIG. 172 (SEQ ID NO:306), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1558 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 171 (SEQ ID NO:305).

In another embodiment, the invention provides isolated PRO1558polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1558 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 26 to about 262 of FIG. 172(SEQ ID NO:306.

In another aspect, the invention concerns an isolated PRO1558polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 26 to about 262, inclusive of FIG. 172 (SEQ ID NO:306.

In a further aspect, the invention concerns an isolated PRO1558polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 26 to about 262, inclusive of FIG. 17(SEQ ID NO:306.

In yet another aspect, the invention concerns an isolated PRO1558polypeptide, comprising the sequence of amino acid residues 1 or about26 to about 262, inclusive of FIG. 172 (SEQ ID NO:306), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1558antibody. Preferably, the PRO1558 fragment retains a qualitativebiological activity of a native PRO1558 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1558 polypeptide having the sequence ofamino acid residues from about 1 or about 26 to about 262, inclusive ofFIG. 172 (SEQ ID NO:306), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1558 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1558 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1558 polypeptide by contactingthe native PRO1558 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1558 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

87. PRO1604

A cDNA clone (DNA71286-1687) has been identified that encodes a novelpolypeptide having homology to hepatoma-derived growth factor (HDGF)designated in the present application as “PRO1604”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1604 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1604 polypeptide having the sequence of amino acidresidues from 1 or about 14 to about 671, inclusive of FIG. 174 (SEQ IDNO:308), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1604 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 104 and about2077, inclusive, of FIG. 173 (SEQ ID NO:307). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203357(DNA71286-1687), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203357 (DNA71286-1687).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 14 to about 671, inclusive of FIG. 174 (SEQ IDNO:308), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1604polypeptide having the sequence of amino acid residues from about 14 toabout 671, inclusive of FIG. 174 (SEQ ID NO:308), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1604 polypeptide, with or withoutthe N-terminal signal sequence, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from amino acid position 1 through about aminoacid position 13 in the sequence of FIG. 174 (SEQ ID NO:308).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 14to about 671, inclusive of FIG. 174 (SEQ ID NO:308), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1604 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1604polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1604 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 14 to 671 of FIG. 174 (SEQ ID NO:308).

In another aspect, the invention concerns an isolated PRO1604polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues14 to about 671, inclusive of FIG. 174 (SEQ ID NO:308).

In a further aspect, the invention concerns an isolated PRO1604polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 14 to671 of FIG. 174 (SEQ ID NO:308).

In yet another aspect, the invention concerns an isolated PRO1604polypeptide, comprising the sequence of amino acid residues 14 to about671, inclusive of FIG. 174 (SEQ ID NO:308), or a fragment thereofsufficient to provide a binding site for an anti-PRO1604 antibody.Preferably, the PRO1604 fragment retains a qualitative biologicalactivity of a native PRO1604 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1604 polypeptide having the sequence ofamino acid residues from about 14 to about 671, inclusive of FIG. 174(SEQ ID NO:308), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1604 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1604 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1604 polypeptide, by contactingthe native PRO1604 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1604 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

88. PRO1491

A cDNA clone (DNA71883-1660) has been identified, having homology tonucleic acid encoding a collapsin protein, that encodes a novelpolypeptide, designated in the present application as “PRO1491”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1491 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1491 polypeptide having the sequence of amino acidresidues from about 1 or about 37 to about 777, inclusive of FIG. 176(SEQ ID NO:310), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1491 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 107 orabout 215 and about 2437, inclusive, of FIG. 175 (SEQ ID NO:309).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203475(DNA71883-1660) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203475 (DNA71883-1660).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 37 to about 777, inclusive of FIG. 176 (SEQ IDNO:310), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 1,670 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1491 polypeptide having the sequence of amino acidresidues from 1 or about 37 to about 777, inclusive of FIG. 176 (SEQ IDNO:310), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1491 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 36 in the sequence of FIG. 176(SEQ ID NO:310).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 37 to about 777, inclusive of FIG. 176 (SEQ ID NO:310), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1491 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 175 (SEQ ID NO:309).

In another embodiment, the invention provides isolated PRO1491polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1491 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 37 to about 777 of FIG. 176(SEQ ID NO:310).

In another aspect, the invention concerns an isolated PRO1491polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 37 to about 777, inclusive of FIG. 176 (SEQ ID NO:310).

In a further aspect, the invention concerns an isolated PRO1491polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 37 to about 777, inclusive of FIG. 176 (SEQ ID NO:310).

In yet another aspect, the invention concerns an isolated PRO1491polypeptide, comprising the sequence of amino acid residues 1 or about37 to about 777, inclusive of FIG. 176 (SEQ ID NO:310), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1491antibody. Preferably, the PRO1491 fragment retains a qualitativebiological activity of a native PRO1491 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1491 polypeptide having the sequence ofamino acid residues from about 1 or about 37 to about 777, inclusive ofFIG. 176 (SEQ ID NO:310), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1491 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1491 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1491 polypeptide by contactingthe native PRO1491 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1491 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

89. PRO1431

A cDNA clone (DNA73401-1633) has been identified having a domain withhomology to SH3 that encodes a novel polypeptide, which has beendesignated in the present application as “PRO1431”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1431 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1431 polypeptide having the sequence of amino acidresidues from about 1 to about 370, inclusive of FIG. 178 (SEQ IDNO:315) or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1431 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between residues 1 to about 1335 andabout 1560 to about 3934, inclusive, of FIG. 177 (SEQ ID NO:314).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns (a) an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203273(DNA73401-1633) or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203273 (DNA73401-1633).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 370, inclusive, of FIG. 178 (SEQ IDNO:315), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 15 nucleotides that is produced byhybridizing a test DNA molecule under stringent conditions with (a) aDNA molecule encoding a PRO1431 polypeptide having the sequence of aminoacid residues from about 1 to about 370, inclusive, of FIG. 178 (SEQ IDNO:315), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 370, inclusive, of FIG. 178 (SEQ ID NO:315), inclusive, of FIG.178 (SEQ ID NO:315).

In another embodiment, the invention provides isolated PRO1431polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1431 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 370, inclusive, of FIG. 178 (SEQ IDNO:315).

In another aspect, the invention concerns an isolated PRO1431polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 370, inclusive, of FIG. 178 (SEQ ID NO:315).

In a further aspect, the invention concerns an isolated PRO1431polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to370 of FIG. 178 (SEQ ID NO:315).

In yet another aspect, the invention concerns an isolated PRO1431 orPRO1432 polypeptide, comprising the sequence of amino acid residues 1 toabout 370, inclusive, or FIG. 178 (SEQ ID NO:315), inclusive, of FIG.178 (SEQ ID NO:315), or a fragment thereof sufficient to provide abinding site for an anti-PRO1431 antibody. Preferably, the PRO1431fragment retains a qualitative biological activity of a native PRO1431polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1431 polypeptide having the sequence ofamino acid residues from about 1 to about 370, inclusive, of FIG. 178(SEQ ID NO:315), inclusive, of FIG. 178 (SEQ ID NO:315), or (b) thecomplement of the DNA molecule of (a), and if the test DNA molecule hasat least about an 80% sequence identity, preferably at least about an85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), (ii) culturing a host cell comprising the test DNA moleculeunder conditions suitable for expression of the polypeptide, and (iii)recovering the polypeptide from the cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1431 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1431 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1431 polypeptide, by contactingthe native PRO1431 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1431 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

90. PRO1563

A cDNA clone (DNA73492-1671) has been identified, having homology tonucleic acid encoding ADAMTS-1 that encodes a novel polypeptide,designated in the present application as “PRO1563”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1563 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1563 polypeptide having the sequence of amino acidresidues from about 1 or about 49 to about 837, inclusive of FIG. 180(SEQ ID NO:317), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1563 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 419 orabout 563 and about 2929, inclusive, of FIGS. 179A-B (SEQ ID NO:316).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203324(DNA73492-1671) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203324 (DNA73492-1671).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 49 to about 837, inclusive of FIG. 180 (SEQ IDNO:317), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1563 polypeptide having the sequence of amino acidresidues from 1 or about 49 to about 837, inclusive of FIG. 180 (SEQ IDNO:317), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1563 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 48 in the sequence of FIG. 180(SEQ ID NO:317).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 49 to about 837, inclusive of FIG. 180 (SEQ ID NO:317), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1563 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIGS. 179A-B (SEQ IDNO:316).

In another embodiment, the invention provides isolated PRO1563polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1563 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 49 to about 837 of FIG. 180(SEQ ID NO:317).

In another aspect, the invention concerns an isolated PRO1563polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 49 to about 837, inclusive of FIG. 180 (SEQ ID NO:317).

In a further aspect, the invention concerns an isolated PRO1563polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 49 to about 837, inclusive of FIG. 180 (SEQ ID NO:317).

In yet another aspect, the invention concerns an isolated PRO1563polypeptide, comprising the sequence of amino acid residues 1 or about49 to about 837, inclusive of FIG. 180 (SEQ ID NO:317), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1563antibody. Preferably, the PRO1563 fragment retains a qualitativebiological activity of a native PRO1563 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1563 polypeptide having the sequence ofamino acid residues from about 1 or about 49 to about 837, inclusive ofFIG. 180 (SEQ ID NO:317), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide thefrom the cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1563 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1563 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1563 polypeptide by contactingthe native PRO1563 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1563 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

91. PRO1565

A cDNA clone (DNA73727-1673) has been identified, having homology tonucleic acid encoding a chondromodulin protein that encodes a novelpolypeptide, designated in the present application as “PRO1565”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1565 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1565 polypeptide having the sequence of amino acidresidues from about 1 or about 41 to about 317, inclusive of FIG. 182(SEQ ID NO:322), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1565 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 59 or about179 and about 1009, inclusive, of FIG. 181 (SEQ ID NO:321). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203459(DNA73727-1673) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203459 (DNA73727-1673).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 41 to about 317, inclusive of FIG. 182 (SEQ IDNO:322), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 410 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1565 polypeptide having the sequence of amino acidresidues from 1 or about 41 to about 317, inclusive of FIG. 182 (SEQ IDNO:322), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1565 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 40 in the sequence of FIG.182 (SEQ ID NO:322). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 25 to about aminoacid position 47 in the PRO1565 amino acid sequence (FIG. 182, SEQ IDNO:322).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 41 to about 317, inclusive of FIG. 182 (SEQ ID NO:322), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1565 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 181 (SEQ ID NO:321).

In another embodiment, the invention provides isolated PRO1565polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1565 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 41 to about 317 of FIG. 182(SEQ ID NO:322).

In another aspect, the invention concerns an isolated PRO1565polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 41 to about 317, inclusive of FIG. 182 (SEQ ID NO:322).

In a further aspect, the invention concerns an isolated PRO1565polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 41 to about 317, inclusive of FIG. 182 (SEQ ID NO:322).

In yet another aspect, the invention concerns an isolated PRO1565polypeptide, comprising the sequence of amino acid residues 1 or about41 to about 317, inclusive of FIG. 182 (SEQ ID NO:322), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1565antibody. Preferably, the PRO1565 fragment retains a qualitativebiological activity of a native PRO1565 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1565 polypeptide having the sequence ofamino acid residues from about 1 or about 41 to about 317, inclusive ofFIG. 182 (SEQ ID NO:322), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1565 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1565 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1565 polypeptide by contactingthe native PRO1565 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1565 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

92. PRO1571

A cDNA clone (DNA73730-1679) has been identified, having homology tonucleic acid encoding the clostridium perfringens enterotoxin receptor(CPE-R) that encodes a novel polypeptide, designated in the presentapplication as “PRO1571”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1571 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1571 polypeptide having the sequence of amino acidresidues from about 1 or about 22 to about 239, inclusive of FIG. 184(SEQ ID NO:324), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1571 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 90 or about153 and about 806, inclusive, of FIG. 183 (SEQ ID NO:323). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203320(DNA73730-1679) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203320 (DNA73730-1679).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 22 to about 239, inclusive of FIG. 184 (SEQ IDNO:324), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 910 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1571 polypeptide having the sequence of amino acidresidues from 1 or about 22 to about 239, inclusive of FIG. 184 (SEQ IDNO:324), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1571 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 21 in the sequence of FIG.184 (SEQ ID NO:324). The transmembrane domains have been tentativelyidentified as extending from about amino acid position 82 to about aminoacid position 103, from about amino acid position 115 to about aminoacid position 141 and from about amino acid position 160 to about aminoacid position 182 in the PRO1571 amino acid sequence (FIG. 184, SEQ IDNO:324).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 22 to about 239, inclusive of FIG. 184 (SEQ ID NO:324), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1571 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 183 (SEQ ID NO:323).

In another embodiment, the invention provides isolated PRO1571polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1571 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 22 to about 239 of FIG. 184(SEQ ID NO:324).

In another aspect, the invention concerns an isolated PRO1571polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 22 to about 239, inclusive of FIG. 184 (SEQ ID NO:324).

In a further aspect, the invention concerns an isolated PRO1571polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 22 to about 239, inclusive of FIG. 184 (SEQ ID NO:324).

In yet another aspect, the invention concerns an isolated PRO1571polypeptide, comprising the sequence of amino acid residues 1 or about22 to about 239, inclusive of FIG. 184 (SEQ ID NO:324), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1571antibody. Preferably, the PRO1571 fragment retains a qualitativebiological activity of a native PRO1571 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1571 polypeptide having the sequence ofamino acid residues from about 1 or about 22 to about 239, inclusive ofFIG. 184 (SEQ ID NO:324), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1571 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1571 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1571 polypeptide by contactingthe native PRO1571 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1571 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

93. PRO1572

A cDNA clone (DNA73734-1680) has been identified that encodes a novelpolypeptide having sequence identity with CPE-R and designated in thepresent application as “PRO1572.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1572 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1572 polypeptide having the sequence of amino acidresidues from 1 or about 24 to about 261, inclusive of FIG. 186 (SEQ IDNO:326), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1572 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 159 and about872, inclusive, of FIG. 185 (SEQ ID NO:325). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203363(DNA73734-1680), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203363 (DNA73734-1680).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 24 to about 261, inclusive of FIG. 186 (SEQ IDNO:326), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1572polypeptide having the sequence of amino acid residues from about 24 toabout 261, inclusive of FIG. 186 (SEQ ID NO:326), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1572 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 23 in the sequence of FIG.186 (SEQ ID NO: 326). The transmembrane domains have been tentativelyidentified as approximately at about 81-100, 121-141 and 173-194 in thePRO1572 amino acid sequence (FIG. 186, SEQ ID NO:326).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 24to about 261, inclusive of FIG. 186 (SEQ ID NO:326), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1572 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1572polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1572 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 24 through 261 of FIG. 186 (SEQ ID NO:326).

In another aspect, the invention concerns an isolated PRO1572polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues24 to about 261, inclusive of FIG. 186 (SEQ ID NO:326).

In a further aspect, the invention concerns an isolated PRO1572polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 24through 261 of FIG. 186 (SEQ ID NO:326).

In yet another aspect, the invention concerns an isolated PRO1572polypeptide, comprising the sequence of amino acid residues 24 to about261, inclusive of FIG. 186 (SEQ ID NO:326), or a fragment thereofsufficient to provide a binding site for an anti-PRO1572 antibody.Preferably, the PRO1572 fragment retains a qualitative biologicalactivity of a native PRO1572 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1572 polypeptidc having the sequence ofamino acid residues from about 24 to about 261, inclusive of FIG. 186(SEQ ID NO:326), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1572 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1572 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1572 polypeptide, by contactingthe native PRO1572 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1572 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

94. PRO1573

A cDNA clone (DNA73735-1681) has been identified that encodes a novelpolypeptide having sequence identity with CPE-R and designated in thepresent application as “PRO1573”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1573 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1573 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 225, inclusive of FIG. 188 (SEQ IDNO:328), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1573 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 148 and about771, inclusive, of FIG. 187 (SEQ ID NO:327). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203356(DNA73735-1681), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203356 (DNA73735-1681).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 18 to about 225, inclusive of FIG. 188 (SEQ IDNO:328), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1573polypeptide having the sequence of amino acid residues from about 18 toabout 225, inclusive of FIG. 188 (SEQ ID NO:328), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1573 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 17 in the sequence of FIG.188 (SEQ ID NO:328). The transmembrane domains have been tentativelyidentified as at approximately 82-101, 118-145 and 164-188 in thePRO1573 amino acid sequence (FIG. 188, SEQ ID NO:328).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 18to about 225, inclusive of FIG. 188 (SEQ ID NO:328), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1573 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1573polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1573 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 18 through 225 of FIG. 188 (SEQ ID NO:328).

In another aspect, the invention concerns an isolated PRO1573polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues18 to about 225, inclusive of FIG. 188 (SEQ ID NO:328).

In a further aspect, the invention concerns an isolated PRO1573polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 18through 225 of FIG. 188 (SEQ ID NO:328).

In yet another aspect, the invention concerns an isolated PRO1573polypeptide, comprising the sequence of amino acid residues 18 to about225, inclusive of FIG. 188 (SEQ ID NO:328), or a fragment thereofsufficient to provide a binding site for an anti-PRO1573 antibody.Preferably, the PRO1573 fragment retains a qualitative biologicalactivity of a native PRO1573 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1573 polypeptide having the sequence ofamino acid residues from about 18 to about 225, inclusive of FIG. 188(SEQ ID NO:328), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1573 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1573 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1573 polypeptide, by contactingthe native PRO1573 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1573 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

95. PRO1488

A cDNA clone (DNA73736-1657) has been identified that encodes a novelpolypeptide having homology to Clostridium perfringens enterotoxinreceptor (CPE-R), designated in the present application as “PRO1488”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1488 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1488 polypeptide having the sequence of amino acidresidues from about 1 to about 220, inclusive of FIG. 190 (SEQ IDNO:330), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1488 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 6 and about665, inclusive, of FIG. 189 (SEQ ID NO:329). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203466(DNA73736-1657), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203466 (DNA73736-1657).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 220, inclusive of FIG. 190 (SEQ IDNO:330), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1488polypeptide having the sequence of amino acid residues from about 1 toabout 220, inclusive of FIG. 190 (SEQ ID NO:330), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1488 polypeptide, with or withoutthe initiating methionine, and its soluble variants (i.e. transmembranedomains deleted or inactivated), or is complementary to such encodingnucleic acid molecule. Transmembrane domains has been tentativelyidentified as being located at about amino acid positions 8-30, 82-102,121-140, and 166-186 in the PRO1488 amino acid sequence (FIG. 190, SEQID NO:330).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 220, inclusive of FIG. 190 (SEQ ID NO:330), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1488 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1488polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1488 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 220 of FIG. 190 (SEQ ID NO:330).

In another aspect, the invention concerns an isolated PRO1488polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 220, inclusive of FIG. 190 (SEQ ID NO:330).

In a further aspect, the invention concerns an isolated PRO1488polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to220 of FIG. 190 (SEQ ID NO:330).

In yet another aspect, the invention concerns an isolated PRO1488polypeptide, comprising the sequence of amino acid residues 1 to about220, inclusive of FIG. 190 (SEQ ID NO:330), or a fragment thereofsufficient to provide a binding site for an anti-PRO1488 antibody.Preferably, the PRO1488 fragment retains a qualitative biologicalactivity of a native PRO1488 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1488 polypeptide having the sequence ofamino acid residues from about 1 to about 220, inclusive of FIG. 190(SEQ ID NO:330), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1488 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1488 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1488 polypeptide, by contactingthe native PRO1488 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1488 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

96. PRO1489

A cDNA clone (DNA73737-1658) has been identified, having homology tonucleic acid encoding the clostridium perfringens enterotoxin receptor(CPE-R) that encodes a novel polypeptide, designated in the presentapplication as “PRO1489”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1489 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1489 polypeptide having the sequence of amino acidresidues from about 1 to about 173, inclusive of FIG. 192 (SEQ IDNO:332), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1489 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 264 andabout 782, inclusive, of FIG. 191 (SEQ ID NO:331). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203412(DNA73737-1658) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203412 (DNA73737-1658).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 to about 173, inclusive of FIG. 192 (SEQ ID NO:332), or(b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 25 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1489 polypeptide having the sequence of amino acidresidues from 1 to about 173, inclusive of FIG. 192 (SEQ ID NO:332), or(b) the complement of the DNA molecule of (a), and, if the DNA moleculehas at least about an 80% sequence identity, prefereably at least aboutan 85% sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1489 polypeptide, with or withoutthe initiating methionine, and its soluble, i.e., transmembrane domaindeleted or inactivated variants, or is complementary to such encodingnucleic acid molecule. The transmembrane domains have been tentativelyidentified as extending from about amino acid position 31 to about aminoacid position 51, from about amino acid position 71 to about amino acidposition 90 and from about amino acid position 112 to about amino acidposition 133 in the PRO1489 amino acid sequence (FIG. 192, SEQ IDNO:332).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 173, inclusive of FIG. 192 (SEQ ID NO:332), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1489 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 191 (SEQ ID NO:331).

In another embodiment, the invention provides isolated PRO1489polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1489 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 to about 173 of FIG. 192 (SEQ IDNO:332).

In another aspect, the invention concerns an isolated PRO1489polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 173, inclusive of FIG. 192 (SEQ ID NO:332).

In a further aspect, the invention concerns an isolated PRO1489polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 toabout 173, inclusive of FIG. 192 (SEQ ID NO:332).

In yet another aspect, the invention concerns an isolated PRO1489polypeptide, comprising the sequence of amino acid residues 1 to about173, inclusive of FIG. 192 (SEQ ID NO: 332), or a fragment thereofsufficient to provide a binding site for an anti-PRO1489 antibody.Preferably, the PRO1489 fragment retains a qualitative biologicalactivity of a native PRO1489 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1489 polypeptide having the sequence ofamino acid residues from about 1 to about 173, inclusive of FIG. 192(SEQ ID NO:332), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1489 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1489 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1489 polypeptide by contactingthe native PRO1489 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1489 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

97. PRO1474

A cDNA clone (DNA73739-1645) has been identified that encodes a novelpolypeptide having sequence identity with ovomucoid and designated inthe present application as “PRO1474.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1474 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1474 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 85, inclusive of FIG. 194 (SEQ IDNO:334), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1474 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 102 and about299, inclusive, of FIG. 193 (SEQ ID NO:333). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203270(DNA73739-1645), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203270 (DNA73739-1645).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 20 to about 85, inclusive of FIG. 194 (SEQ IDNO:334), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1474polypeptide having the sequence of amino acid residues from about 20 toabout 85, inclusive of FIG. 194 (SEQ ID NO:334), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 20to about 85, inclusive of FIG. 194 (SEQ ID NO:334), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1474 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1474polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1474 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 20 through 85 of FIG. 194 (SEQ ID NO:334).

In another aspect, the invention concerns an isolated PRO1474polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues20 to about 85, inclusive of FIG. 194 (SEQ ID NO:334).

In a further aspect, the invention concerns an isolated PRO1474polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 20through 85 of FIG. 194 (SEQ ID NO:334).

In yet another aspect, the invention concerns an isolated PRO1474polypeptide, comprising the sequence of amino acid residues 20 to about85, inclusive of FIG. 194 (SEQ ID NO:334), or a fragment thereofsufficient to provide a binding site for an anti-PRO1474 antibody.Preferably, the PRO1474 fragment retains a qualitative biologicalactivity of a native PRO1474 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1474 polypeptide having the sequence ofamino acid residues from about 20 to about 85, inclusive of FIG. 194(SEQ ID NO:334), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1474 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1474 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1474 polypeptide, by contactingthe native PRO1474 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1474 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

98. PRO1508

A cDNA clone (DNA73742-1662) has been identified that encodes a novelsecreted polypeptide and designated in the present application as“PRO1508.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1508 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1508 polypeptide having the sequence of amino acidresidues from 1 or about 31 to about 148, inclusive of FIG. 196 (SEQ IDNO:336), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1508 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 160 and about513, inclusive, of FIG. 195 (SEQ ID NO:335). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203316(DNA73742-1662), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203316 (DNA73742-1662).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 31 to about 148, inclusive of FIG. 196 (SEQ IDNO:336), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1508polypeptide having the sequence of amino acid residues from about 31 toabout 148, inclusive of FIG. 196 (SEQ ID NO:336), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1508 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 30 in the sequence of FIG. 196 (SEQ IDNO:336).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 31to about 148, inclusive of FIG. 196 (SEQ ID NO:336), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1508 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1508polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1508 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 31 to 148 of FIG. 196 (SEQ ID NO:336).

In another aspect, the invention concerns an isolated PRO1508polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues31 to about 148, inclusive of FIG. 196 (SEQ ID NO:336).

In a further aspect, the invention concerns an isolated PRO1508polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 31 to148 of FIG. 196 (SEQ ID NO:336).

In yet another aspect, the invention concerns an isolated PRO1508polypeptide, comprising the sequence of amino acid residues 31 to about148, inclusive of FIG. 196 (SEQ ID NO:336), or a fragment thereofsufficient to provide a binding site for an anti-PRO1508 antibody.Preferably, the PRO108 fragment retains a qualitative biologicalactivity of a native PRO1508 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1508 polypeptide having the sequence ofamino acid residues from about 31 to about 148, inclusive of FIG. 196(SEQ ID NO:336), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

99. PRO1555

A cDNA clone (DNA73744-1665) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1555”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1555 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1555 polypeptide having the sequence of amino acidresidues from 1 or about 32 to about 246, inclusive of FIG. 198 (SEQ IDNO:338), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1555 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 83 and about827, inclusive, of FIG. 197 (SEQ ID NO:337). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203322(DNA73744-1665), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203322 (DNA73744-1665).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 32 to about 246, inclusive of FIG. 198 (SEQ IDNO:338), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1555polypeptide having the sequence of amino acid residues from about 32 toabout 246, inclusive of FIG. 198 (SEQ ID NO:338), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1555 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble variants (i.e. transmembrane domains deleted or inactivated), oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 31 in the sequence of FIG.198 (SEQ ID NO:338). Two transmembrane domains have been tentativelyidentified as extending from about amino acid position 1 to about aminoacid position 32, and from about amino acid position 195 through aboutamino acid position 217, in the PRO1555 amino acid sequence (FIG. 198,SEQ ID NO:338).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 32to about 246, inclusive of FIG. 198 (SEQ ID NO:338), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1555 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1555polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1555 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 32 to 246 of FIG. 198 (SEQ ID NO:338).

In another aspect, the invention concerns an isolated PRO1555polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues32 to about 246, inclusive of FIG. 198 (SEQ ID NO:338).

In a further aspect, the invention concerns an isolated PRO1555polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 32 to246 of FIG. 198 (SEQ ID NO:338).

In yet another aspect, the invention concerns an isolated PRO1555polypeptide, comprising the sequence of amino acid residues 32 to about246, inclusive of FIG. 198 (SEQ ID NO:338), or a fragment thereofsufficient to provide a binding site for an anti-PRO1555 antibody.Preferably, the PRO1555 fragment retains a qualitative biologicalactivity of a native PRO1555 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1555 polypeptide having the sequence ofamino acid residues from about 32 to about 246, inclusive of FIG. 198(SEQ ID NO:338), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

100. PRO1485

A cDNA clone (DNA73746-1654) has been identified that encodes a novelpolypeptide having sequence identity with lysozyme, and moreparticularly, lysozyme C precursor, and designated in the presentapplication as “PRO1485.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1485 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1485 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 148, inclusive of FIG. 200 (SEQ IDNO:340), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1485 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 205 and about594, inclusive, of FIG. 199 (SEQ ID NO:339). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203411(DNA73746-1654), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203411 (DNA73746-1654).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 148, inclusive of FIG. 200 (SEQ IDNO:340), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1485polypeptide having the sequence of amino acid residues from about 19 toabout 148, inclusive of FIG. 200 (SEQ ID NO:340), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 148, inclusive of FIG. 200 (SEQ ID NO:340), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1485 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1485polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1485 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 through 148 of FIG. 200 (SEQ ID NO:340).

In another aspect, the invention concerns an isolated PRO1485polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 148, inclusive of FIG. 200 (SEQ ID NO:340).

In a further aspect, the invention concerns an isolated PRO1485polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19through 148 of FIG. 200 (SEQ ID NO:340).

In yet another aspect, the invention concerns an isolated PRO1485polypeptide, comprising the sequence of amino acid residues 19 to about148, inclusive of FIG. 200 (SEQ ID NO:340), or a fragment thereofsufficient to provide a binding site for an anti-PRO1485 antibody.Preferably, the PRO1485 fragment retains a qualitative biologicalactivity of a native PRO1485 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1485 polypeptide having the sequence ofamino acid residues from about 19 to about 148, inclusive of FIG. 200(SEQ ID NO:340), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1485 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1485 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1485 polypeptide, by contactingthe native PRO1485 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1485 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

101. PRO1564

A cDNA clone (DNA73760-1672) has been identified, having homology tonucleic acid encoding an N-acetylgalactosaminyltransferase protein thatencodes a novel polypeptide, designated in the present application as“PRO1564”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1564 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1564 polypeptide having the sequence of amino acidresidues from about 1 or about 29 to about 639, inclusive of FIG. 202(SEQ ID NO:347), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1564 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 462 orabout 546 and about 2378, inclusive, of FIG. 201 (SEQ ID NO:346).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203314(DNA73760-1672) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203314 (DNA73760-1672).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 29 to about 639, inclusive of FIG. 202 (SEQ IDNO:347), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1564 polypeptide having the sequence of amino acidresidues from 1 or about 29 to about 639, inclusive of FIG. 202 (SEQ IDNO:347), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1564 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 28 in the sequence of FIG.202 (SEQ ID NO:347). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 11 to about aminoacid position 36 in the PRO1564 amino acid sequence (FIG. 202, SEQ IDNO:347).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 29 to about 639, inclusive of FIG. 202 (SEQ ID NO:347), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1564 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 201 (SEQ ID NO:346).

In another embodiment, the invention provides isolated PRO1564polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1564 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 29 to about 639 of FIG. 202(SEQ ID NO:347).

In another aspect, the invention concerns an isolated PRO1564polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 29 to about 639, inclusive of FIG. 202 (SEQ ID NO:347).

In a further aspect, the invention concerns an isolated PRO564polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 29 to about 639, inclusive of FIG. 202 (SEQ ID NO:347).

In yet another aspect, the invention concerns an isolated PRO1564polypeptide, comprising the sequence of amino acid residues 1 or about29 to about 639, inclusive of FIG. 202 (SEQ ID NO:347), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1564antibody. Preferably, the PRO1564 fragment retains a qualitativebiological activity of a native PRO1564 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1564 polypeptide having the sequence ofamino acid residues from about 1 or about 29 to about 639, inclusive ofFIG. 202 (SEQ ID NO:347), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1564 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1564 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1564 polypeptide by contactingthe native PRO1564 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1564 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

102. PRO1755

A cDNA clone (DNA76396-1698) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1755”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO1755 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1755 polypeptide having he sequence of amino acid residuesfrom 1 or about 32 to about 276, inclusive of FIG. 204 (SEQ ID NO:352),or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1755 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 151 and about885, inclusive, of FIG. 203 (SEQ ID NO:351). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203471(DNA76396-1698), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203471 (DNA76396-1698).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 32 to about 276, inclusive of FIG. 204 (SEQ IDNO:352), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1755polypeptide having the sequence of amino acid residues from about 32 toabout 276, inclusive of FIG. 204 (SEQ ID NO:352), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1755 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble variants (i.e. transmembrane domain deleted or inactivated), oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 31 in the sequence of FIG.204 (SEQ ID NO:352). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 178 to aboutamino acid position 198 in the PRO1755 amino acid sequence (FIG. 204,SEQ ID NO:352).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 32to about 276, inclusive of FIG. 204 (SEQ ID NO:352), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1755 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1755polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1755 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 32 to 276 of FIG. 204 (SEQ ID NO:352).

In another aspect, the invention concerns an isolated PRO1755polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues32 to about 276, inclusive of FIG. 204 (SEQ ID NO:352).

In a further aspect, the invention concerns an isolated PRO1755polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 32 to276 of FIG. 204 (SEQ ID NO:352).

In yet another aspect, the invention concerns an isolated PRO1755polypeptide, comprising the sequence of amino acid residues 32 to about276, inclusive of FIG. 204 (SEQ ID NO:352), or a fragment thereofsufficient to provide a binding site for an anti-PRO1755 antibody.Preferably, the PRO1755 fragment retains a qualitative biologicalactivity of a native PRO1755 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1755 polypeptide having the sequence ofamino acid residues from about 32 to about 276, inclusive of FIG. 204(SEQ ID NO:352), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1755 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1755 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1755 polypeptide, by contactingthe native PRO1755 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1755 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

103. PRO1757

A cDNA clone (DNA76398-1699) has been identified that encodes a noveltransmembrane polypeptide, designated in the present application as“PRO1757”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO1757 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1757 polypeptide having the sequence of amino acidresidues from about 1 or about 20 to about 121, inclusive of FIG. 206(SEQ ID NO:354), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1757 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 59 or about116 and about 121, inclusive, of FIG. 205 (SEQ ID NO:353). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203474(DNA76398-1699) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No.203474 (DNA76398-1699).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 20 to about 121, inclusive of FIG. 206 (SEQ IDNO:354), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 125 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1757 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 121, inclusive of FIG. 206 (SEQ IDNO:354), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1757 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 19 in the sequence of FIG.206 (SEQ ID NO:354). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 91 to about aminoacid position 110 in the PRO1757 amino acid sequence (FIG. 206, SEQ IDNO:354).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 20 to about 121, inclusive of FIG. 206 (SEQ ID NO:354), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1757 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 205 (SEQ ID NO:353).

In another embodiment, the invention provides isolated PRO1757polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1757 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 20 to about 121 of FIG. 206(SEQ ID NO:354).

In another aspect, the invention concerns an isolated PRO1757polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 20 to about 121, inclusive of FIG. 206 (SEQ ID NO:354).

In a further aspect, the invention concerns an isolated PRO1757polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 20 to about 121, inclusive of FIG. 206 (SEQ ID NO:354).

In yet another aspect, the invention concerns an isolated PRO1757polypeptide, comprising the sequence of amino acid residues 1 or about20 to about 121, inclusive of FIG. 206 (SEQ ID NO:354), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1757antibody. Preferably, the PRO1757 fragment retains a qualitativebiological activity of a native PRO1757 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1757 polypeptide having the sequence ofamino acid residues from about 1 or about 20 to about 121, inclusive ofFIG. 206 (SEQ ID NO:354), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1757 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1757 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1757 polypeptide by contactingthe native PRO1757 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1757 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

104. PRO1758

A cDNA clone (DNA76399-1700) has been identified that encodes a novelsecreted polypeptide designated in the present application as “PRO1758”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1758 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1758 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 157, inclusive of FIG. 208 (SEQ IDNO:356), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1758 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 123 and about548, inclusive, of FIG. 207 (SEQ ID NO:355). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203472(DNA76399-1700), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203472 (DNA76399-1700).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 16 to about 157, inclusive of FIG. 208 (SEQ IDNO:356), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1758polypeptide having the sequence of amino acid residues from about 16 toabout 157, inclusive of FIG. 208 (SEQ ID NO:356), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1758 polypeptide, with or withoutthe N-terminal signal sequence, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from amino acid position 1 through about aminoacid position 15 in the sequence of FIG. 208 (SEQ ID NO:356).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 16to about 157, inclusive of FIG. 208 (SEQ ID NO:356), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1758 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1758polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1758 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 16 to 157 of FIG. 208 (SEQ ID NO:356).

In another aspect, the invention concerns an isolated PRO1758polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues16 to about 157, inclusive of FIG. 208 (SEQ ID NO:356).

In a further aspect, the invention concerns an isolated PRO1758polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 16 to157 of FIG. 208 (SEQ ID NO:356).

In yet another aspect, the invention concerns an isolated PRO1758polypeptide, comprising the sequence of amino acid residues 16 to about157, inclusive of FIG. 208 (SEQ ID NO:356), or a fragment thereofsufficient to provide a binding site for an anti-PRO1758 antibody.Preferably, the PRO1758 fragment retains a qualitative biologicalactivity of a native PRO1758 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1758 polypeptide having the sequence ofamino acid residues from about 16 to about 157, inclusive of FIG. 208(SEQ ID NO:356), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

105. PRO1575

A cDNA clone (DNA76401-1683) has been identified that encodes a novelpolypeptide having homology to protein disulfide isomerase anddesignated in the present application as “PRO1575.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1575 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1575 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 273, inclusive of FIG. 210 (SEQ IDNO:358), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1575 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 82 and about840, inclusive, of FIG. 209 (SEQ ID NO:357). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203360(DNA76401-1683), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203360 (DNA76401-1683).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 21 to about 273, inclusive of FIG. 210 (SEQ IDNO:358), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1575polypeptide having the sequence of amino acid residues from about 21 toabout 273, inclusive of FIG. 210 (SEQ ID NO:358), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1575 polypeptide, its solublevariants, (i.e. transmembrane domain and/or signal peptide deleted orinactivated) or is complementary to such encoding nucleic acid molecule.The signal peptide has been tentatively identified as extending fromamino acid position 1 through about amino acid position 20 in thesequence of FIG. 210 (SEQ ID NO:358). The transmembrane domain has beententatively identified as extending from about amino acid position 143to about amino acid position 162 in the PRO1575 amino acid sequence(FIG. 210, SEQ ID NO:358).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 21to about 273, inclusive of FIG. 210 (SEQ ID NO:358), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1575 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1575polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1575 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 21 to 273 of FIG. 210 (SEQ ID NO:358).

In another aspect, the invention concerns an isolated PRO1575polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues21 to about 273, inclusive of FIG. 210 (SEQ ID NO:358).

In a further aspect, the invention concerns an isolated PRO1575polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 21 to273 of FIG. 210 (SEQ ID NO:358).

In yet another aspect, the invention concerns an isolated PRO1575polypeptide, comprising the sequence of amino acid residues 21 to about273, inclusive of FIG. 210 (SEQ ID NO:358), or a fragment thereofsufficient to provide a binding site for an anti-PRO1575 antibody.Preferably, the PRO1575 fragment retains a qualitative biologicalactivity of a native PRO1575 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1575 polypeptide having the sequence ofamino acid residues from about 21 to about 273, inclusive of FIG. 210(SEQ ID NO:358), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1575 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1575 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1575 polypeptide, by contactingthe native PRO1575 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1575 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

106. PRO1787

A cDNA clone (DNA76510-2504) has been identified that encodes a novelpolypeptide having sequence identity with myelin p0 and designated inthe present application as “PRO1787.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1787 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1787 polypeptide having the sequence of amino acidresidues from 1 or about 38 to about 269, inclusive of FIG. 212 (SEQ IDNO:364), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1787 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 274 and about969, inclusive, of FIG. 211 (SEQ ID NO:363). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203477(DNA76510-2504), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC DepositNo.203477 (DNA76510-2504).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 38 to about 269, inclusive of FIG. 212 (SEQ IDNO:364), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1787polypeptide having the sequence of amino acid residues from about 38 toabout 269, inclusive of FIG. 212 (SEQ ID NO:364), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1787 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 37 in the sequence of FIG.212 (SEQ ID NO:364). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 161 through aboutamino acid position 183 in the PRO1787 amino acid sequence (FIG. 212,SEQ ID NO:364).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 38to about 269, inclusive of FIG. 212 (SEQ ID NO:364), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1787 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1787polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1787 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 38 through 269 of FIG. 212 (SEQ ID NO:364).

In another aspect, the invention concerns an isolated PRO1787polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues38 to about 269, inclusive of FIG. 212 (SEQ ID NO:364).

In a further aspect, the invention concerns an isolated PRO1787polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 38through 269 of FIG. 212 (SEQ ID NO:364).

In yet another aspect, the invention concerns an isolated PRO1787polypeptide, comprising the sequence of amino acid residues 38 to about269, inclusive of FIG. 212 (SEQ ID NO:364), or a fragment thereofsufficient to provide a binding site for an anti-PRO1787 antibody.Preferably, the PRO1787 fragment retains a qualitative biologicalactivity of a native PRO1787 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1787 polypeptide having the sequence ofamino acid residues from about 38 to about 269, inclusive of FIG. 212(SEQ ID NO:364), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1787 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1787 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1787 polypeptide, by contactingthe native PRO1787 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1787 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

107. PRO1781

A cDNA clone (DNA76522-2500) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1781”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1781 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1781 polypeptide having the sequence of amino acidresidues from 1 or about 20 to about 373, inclusive of FIG. 214 (SEQ IDNO:366), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1781 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 78 and about1139, inclusive, of FIG. 213 (SEQ ID NO:365). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203469(DNA76522-2500), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203469 (DNA76522-2500).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 20 to about 373, inclusive of FIG. 214 (SEQ IDNO:366), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1781polypeptide having the sequence of amino acid residues from about 20 toabout 373, inclusive of FIG. 214 (SEQ ID NO:36), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1781 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble variants (i.e. transmembrane domain deleted or inactivated), oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 19 in the sequence of FIG.214 (SEQ ID NO:366). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 39 to about aminoacid position 60 in the PRO1781 amino acid sequence (FIG. 214, SEQ IDNO:366).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 20to about 373, inclusive of FIG. 214 (SEQ ID NO:366), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1781 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1781polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1781 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 20 to 373 of FIG. 214 (SEQ ID NO:366).

In another aspect, the invention concerns an isolated PRO1781polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues20 to about 373, inclusive of FIG. 214 (SEQ ID NO:366).

In a further aspect, the invention concerns an isolated PRO1781polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 20 to373 of FIG. 214 (SEQ ID NO:366).

In yet another aspect, the invention concerns an isolated PRO1781polypeptide, comprising the sequence of amino acid residues 20 to about373, inclusive of FIG. 214 (SEQ ID NO:366), or a fragment thereofsufficient to provide a binding site for an anti-PRO1781 antibody.Preferably, the PRO1781 fragment retains a qualitative biologicalactivity of a native PRO1781 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1781 polypeptide having the sequence ofamino acid residues from about 20 to about 373, inclusive of FIG. 214(SEQ ID NO:366), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

108. PRO1556

A cDNA clone (DNA76529-1666) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1556”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1556 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1556 polypeptide having the sequence of amino acidresidues from 1 or about 25 to about 269, inclusive of FIG. 216 (SEQ IDNO:372), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1556 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 160 and about891, inclusive, of FIG. 215 (SEQ ID NO:371). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203315(DNA76529-1666), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203315 (DNA76529-1666).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 25 to about 269, inclusive of FIG. 216 (SEQ IDNO:372), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1556polypeptide having the sequence of amino acid residues from about 25 toabout 269, inclusive of FIG. 216 (SEQ ID NO:372), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1556 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble variants (i.e. transmembrane domains deleted or inactivated), oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 24 in the sequence of FIG.216 (SEQ ID NO:372). Two transmembrane domains have been tentativelyidentified as extending from about amino acid position 11 to about aminoacid position 25 and from about amino acid position 226 to about aminoacid position 243 in the PRO1556 amino acid sequence (FIG. 216, SEQ IDNO:372).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 25to about 269, inclusive of FIG. 216 (SEQ ID NO:372), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1556 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1556polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1556 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 25 to 269 of FIG. 216 (SEQ ID NO:372).

In another aspect, the invention concerns an isolated PRO1556polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues25 to about 269, inclusive of FIG. 216 (SEQ ID NO:372).

In a further aspect, the invention concerns an isolated PRO1556polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 25 to269 of FIG. 216 (SEQ ID NO:372).

In yet another aspect, the invention concerns an isolated PRO1556polypeptide, comprising the sequence of amino acid residues 25 to about269, inclusive of FIG. 216 (SEQ ID NO:372), or a fragment thereofsufficient to provide a binding site for an anti-PRO1556 antibody.Preferably, the PRO1556 fragment retains a qualitative biologicalactivity of a native PRO1556 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1556 polypeptide having the sequence ofamino acid residues from about 25 to about 269, inclusive of FIG. 216(SEQ ID NO:372), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1556 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1556 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1556 polypeptide, by contactingthe native PRO1556 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1556 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

109. PRO1759

A cDNA clone (DNA76531-1701) has been identified that encodes a novelpolypeptide having multiple transmembrane domains, designated in thepresent application as “PRO1759.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1759 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1759 polypeptide having the sequence of amino acidresidues from 1 or about 19 to about 450, inclusive of FIG. 218 (SEQ IDNO:374), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1759 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 179 and about1474, inclusive, of FIG. 217 (SEQ ID NO:373). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203465(DNA76531-1701), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203465 (DNA76531-1701).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 19 to about 450, inclusive of FIG. 218 (SEQ IDNO:374), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1759polypeptide having the sequence of amino acid residues from about 19 toabout 450, inclusive of FIG. 218 (SEQ ID NO:374), or (b) the complementof thc DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1759 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domains deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 18 in the sequence of FIG.218 (SEQ ID NO:374). The transmembrane domains have been tentativelyidentified as being at about amino acids 1-19 (possibly a signalpeptide), 41-55, 75-94, 127-143, 191-213, 249-270, 278-299, 314-330,343-359, 379-394, and 410-430 in the PRO1759 amino acid sequence (FIG.218, SEQ ID NO:374).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 19to about 450, inclusive of FIG. 218 (SEQ ID NO:374), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1759 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1759polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1759 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 19 through 450 of FIG. 218 (SEQ ID NO:374).

In another aspect, the invention concerns an isolated PRO1759polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues19 to about 450, inclusive of FIG. 218 (SEQ ID NO:374).

In a further aspect, the invention concerns an isolated PRO1759polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 19through 450 of FIG. 218 (SEQ ID NO:374).

In yet another aspect, the invention concerns an isolated PRO1759polypeptide, comprising the sequence of amino acid residues 19 to about450, inclusive of FIG. 218 (SEQ ID NO:374), or a fragment thereofsufficient to provide a binding site for an anti-PRO1759 antibody.Preferably, the PRO1759 fragment retains a qualitative biologicalactivity of a native PRO1759 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1759 polypeptide having the sequence ofamino acid residues from about 19 to about 450, inclusive of FIG. 218(SEQ ID NO:374), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1759 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1759 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1759 polypeptide, by contactingthe native PRO1759 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1759 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

110. PRO1760

A cDNA clone (DNA76532-1702) has been identified that encodes a novelsecreted polypeptide, designated in the present application as“PRO1760.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO1760 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1760 polypeptide having the sequence of amino acidresidues from 1 or about 21 to about 188, inclusive of FIG. 220 (SEQ IDNO:376), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1760 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 120 and about623, inclusive, of FIG. 219 (SEQ ID NO:375). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203473(DNA76532-1702), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203473 (DNA76532-1702).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 21 to about 188, inclusive of FIG. 220 (SEQ IDNO:376), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1760polypeptide having the sequence of amino acid residues from about 21 toabout 188, inclusive of FIG. 220 (SEQ ID NO:376), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 21to about 188, inclusive of FIG. 220 (SEQ ID NO: 376), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1760 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1760polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1760 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 21 through 188 of FIG. 220 (SEQ ID NO:376).

In another aspect, the invention concerns an isolated PRO1760polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues21 to about 188, inclusive of FIG. 220 (SEQ ID NO:376).

In a further aspect, the invention concerns an isolated PRO1760polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 21through 188 of FIG. 220 (SEQ ID NO:376).

In yet another aspect, the invention concerns an isolated PRO1760polypeptide, comprising the sequence of amino acid residues 21 to about188, inclusive of FIG. 220 (SEQ ID NO:376), or a fragment thereofsufficient to provide a binding site for an anti-PRO1760 antibody.Preferably, the PRO1760 fragment retains a qualitative biologicalactivity of a native PRO1760 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1760 polypeptide having the sequence ofamino acid residues from about 21 to about 188, inclusive of FIG. 220(SEQ ID NO:376), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1760 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1760 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1760 polypeptide, by contactingthe native PRO1760 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1760 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

111. PRO1561

A cDNA clone (DNA76538-1670) has been identified, having homology tonucleic acid encoding human phospholipase A2 protein that encodes anovel polypeptide, designated in the present application as “PRO1561”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1561 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1561 polypeptide having the sequence of amino acidresidues from about 1 or about 18 to about 116, inclusive of FIG. 222(SEQ ID NO:378), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1561 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 29 or about80 and about 376, inclusive, of FIG. 221 (SEQ ID NO:377). Preferably,hybridization occurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203313(DNA76538-1670) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203313 (DNA76538-1670).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 18 to about 116, inclusive of FIG. 222 (SEQ IDNO:378), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 100 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1561 polypeptide having the sequence of amino acidresidues from 1 or about 18 to about 116, inclusive of FIG. 222 (SEQ IDNO:378), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1561 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 17 in the sequence of FIG.222 (SEQ ID NO:378). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 1 to about aminoacid position 24 in the PRO1561 amino acid sequence (FIG. 222, SEQ IDNO:378).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 18 to about 116, inclusive of FIG. 222 (SEQ ID NO:378), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1561 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 221 (SEQ ID NO:377).

In another embodiment, the invention provides isolated PRO1561polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1561 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 18 to about 116 of FIG. 222(SEQ ID NO:378).

In another aspect, the invention concerns an isolated PRO1561polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 18 to about 116, inclusive of FIG. 222 (SEQ ID NO:378).

In a further aspect, the invention concerns an isolated PRO1561polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 18 to about 116, inclusive of FIG. 222 (SEQ ID NO:378).

In yet another aspect, the invention concerns an isolated PRO1561polypeptide, comprising the sequence of amino acid residues 1 or about18 to about 116, inclusive of FIG. 222 (SEQ ID NO:378), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1561antibody. Preferably, the PRO1561 fragment retains a qualitativebiological activity of a native PRO1561 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1561 polypeptide having the sequence ofamino acid residues from about 1 or about 18 to about 116, inclusive ofFIG. 222 (SEQ ID NO:378), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1561 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1561 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1561 polypeptide by contactingthe native PRO1561 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1561 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

112. PRO1567

A cDNA clone (DNA76541-1675) has been identified that encodes a novelpolypeptide having homology to the expression product of the colonspecific gene, CSG6, and is designated in the present application as“PRO1567”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1567 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1567 polypeptide having the sequence of amino acidresidues from 1 or about 23 to about 178, inclusive of FIG. 224 (SEQ IDNO:383), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1567 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 175 and about642, inclusive, of FIG. 223 (SEQ ID NO:382). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203409(DNA76541-1675), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203409 (DNA76541-1675).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 23 to about 178, inclusive of FIG. 224 (SEQ IDNO:383), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1567polypeptide having the sequence of amino acid residues from about 23 toabout 178, inclusive of FIG. 224 (SEQ ID NO:383), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1567 polypeptide, with or withoutthe N-terminal signal sequence, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from amino acid position 1 through about aminoacid position 22 in the sequence of FIG. 224 (SEQ ID NO:383).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 23to about 178, inclusive of FIG. 224 (SEQ ID NO:383), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1567 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1567polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1567 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 23 to 178 of FIG. 224 (SEQ ID NO:383).

In another aspect, the invention concerns an isolated PRO1567polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues23 to about 178, inclusive of FIG. 224 (SEQ ID NO:383).

In a further aspect, the invention concerns an isolated PRO1567polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 23 to178 of FIG. 224 (SEQ ID NO:383).

In yet another aspect, the invention concerns an isolated PRO1567polypeptide, comprising the sequence of amino acid residues 23 to about178, inclusive of FIG. 224 (SEQ ID NO:383), or a fragment thereofsufficient to provide a binding site for an anti-PRO1567 antibody.Preferably, the PRO1567 fragment retains a qualitative biologicalactivity of a native PRO1567 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1567 polypeptide having the sequence ofamino acid residues from about 23 to about 178, inclusive of FIG. 224(SEQ ID NO:383), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1567 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1567 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1567 polypeptide, by contactingthe native PRO1567 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1567 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

113. PRO1693

A cDNA clone (DNA77301-1708) has been identified, having homology tonucleic acid encoding an insulin-like growth factor binding protein thatencodes a novel polypeptide, designated in the present application as“PRO1693”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1693 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1693 polypeptide having the sequence of amino acidresidues from about 1 or about 34 to about 513, inclusive of FIG. 226(SEQ ID NO:385), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1693 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 508 orabout 607 and about 2046, inclusive, of FIG. 225 (SEQ ID NO:384).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203407(DNA77301-1708) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203407 (DNA77301-1708).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 34 to about 513, inclusive of FIG. 226 (SEQ IDNO:385), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 175 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1693 polypeptide having the sequence of amino acidresidues from 1 or about 34 to about 513, inclusive of FIG. 226 (SEQ IDNO:385), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1693 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 33 in the sequence of FIG.226 (SEQ ID NO:385). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 420 to aboutamino acid position 442 in the PRO1693 amino acid sequence (FIG. 226,SEQ ID NO:385).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding polypeptide scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 34 to about 513, inclusive of FIG. 226 (SEQ ID NO:385), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1693 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 225 (SEQ ID NO:384).

In another embodiment, the invention provides isolated PRO1693polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1693 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 34 to about 513 of FIG. 226(SEQ ID NO:385).

In another aspect, the invention concerns an isolated PRO1693polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 34 to about 513, inclusive of FIG. 226 (SEQ ID NO:385).

In a further aspect, the invention concerns an isolated PRO1693polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 34 to about 513, inclusive of FIG. 226 (SEQ ID NO:385).

In yet another aspect, the invention concerns an isolated PRO1693polypeptide, comprising the sequence of amino acid residues 1 or about34 to about 513, inclusive of FIG. 226 (SEQ ID NO:385), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1693antibody. Preferably, the PRO1693 fragment retains a qualitativebiological activity of a native PRO1693 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1693 polypeptide having the sequence ofamino acid residues from about 1 or about 34 to about 513, inclusive ofFIG. 226 (SEQ ID NO:385), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1693 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1693 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1693 polypeptide by contactingthe native PRO1693 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1693 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

114. PRO1784

A cDNA clone (DNA77303-2502) has been identified that encodes a noveltransmembrane polypeptide designated in the present application as“PRO1784.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1784 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1784 polypeptide having the sequence of amino acidresidues from 1 or about 30 to about 146, inclusive of FIG. 228 (SEQ IDNO:390), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1784 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 155 and about505, inclusive, of FIG. 227 (SEQ ID NO:389). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203479(DNA77303-2502), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203479 (DNA77303-2502).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 30 to about 146, inclusive of FIG. 228 (SEQ IDNO:390), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1784polypeptide having the sequence of amino acid residues from about 30 toabout 146, inclusive of FIG. 228 (SEQ ID NO:390), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1784 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 29 in the sequence of FIG.228 (SEQ ID NO:390). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 52 through aboutamino acid position 70 in the PRO1784 amino acid sequence (FIG. 228, SEQID NO:390).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 30to about 146, inclusive of FIG. 228 (SEQ ID NO:390), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1784 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1784polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1784 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 30 through 146 of FIG. 228 (SEQ ID NO:390).

In another aspect, the invention concerns an isolated PRO1784polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues30 to about 146, inclusive of FIG. 228 (SEQ ID NO:390).

In a further aspect, the invention concerns an isolated PRO1784polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 30through 146 of FIG. 228 (SEQ ID NO:390).

In yet another aspect, the invention concerns an isolated PRO1784polypeptide, comprising the sequence of amino acid residues 30 to about146, inclusive of FIG. 228 (SEQ ID NO:390), or a fragment thereofsufficient to provide a binding site for an anti-PRO1784 antibody.Preferably, the PRO1784 fragment retains a qualitative biologicalactivity of a native PRO1784 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1784 polypeptide having the sequence ofamino acid residues from about 30 to about 146, inclusive of FIG. 228(SEQ ID NO:390), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1784 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1784 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1784 polypeptide, by contactingthe native PRO1784 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1784 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

115. PRO1605

A cDNA clone (DNA77648-1688) has been identified, having homology tonucleic acid encoding a glycosyltransferase protein that encodes a novelpolypeptide, designated in the present application as “PRO1605”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1605 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1605 polypeptide having the sequence of amino acidresidues from about 1 or about 27 to about 140, inclusive of FIG. 230(SEQ ID NO:395), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1605 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 425 orabout 503 and about 844, inclusive, of FIG. 229 (SEQ ID NO:394).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit 203408(DNA77648-1688) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203408 (DNA77648-t688).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 27 to about 140, inclusive of FIG. 230 (SEQ IDNO:395), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 380 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1605 polypeptide having the sequence of amino acidresidues from 1 or about 27 to about 140, inclusive of FIG. 230 (SEQ IDNO:395), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1605 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 26 in the sequence of FIG. 230(SEQ ID NO:395).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 27 to about 140, inclusive of FIG. 230 (SEQ ID NO:395), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1605 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 229 (SEQ ID NO:394).

In another embodiment, the invention provides isolated PRO1605polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1605 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 27 to about 140 of FIG. 230(SEQ ID NO:395).

In another aspect, the invention concerns an isolated PRO1605polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 27 to about 140, inclusive of FIG. 230 (SEQ ID NO:395).

In a further aspect, the invention concerns an isolated PRO1605polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 27 to about 140, inclusive of FIG. 230 (SEQ ID NO:395).

In yet another aspect, the invention concerns an isolated PRO1605polypeptide, comprising the sequence of amino acid residues 1 or about27 to about 140, inclusive of FIG. 230 (SEQ ID NO:395), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1605antibody. Preferably, the PRO1605 fragment retains a qualitativebiological activity of a native PRO1605 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1605 polypeptide having the sequence ofamino acid residues from about 1 or about 27 to about 140, inclusive ofFIG. 230 (SEQ ID NO:395), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1605 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1605 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1605 polypeptide by contactingthe native PRO1605 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1605 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

116. PRO1788

A cDNA clone (DNA77652-2505) has been identified that encodes a novelpolypeptide having homology to leucine-rich repeat proteins anddesignated in the present application as “PRO1788.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1788 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1788 polypeptide having the sequence of amino acidresidues from 1 or about 17 to about 353, inclusive of FIG. 232 (SEQ IDNO:397), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1788 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 112 and about1122, inclusive, of FIG. 231 (SEQ ID NO:396). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203480(DNA77652-2505), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203480 (DNA77652-2505).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 17 to about 353, inclusive of FIG. 232 (SEQ IDNO:397), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1788polypeptide having the sequence of amino acid residues from about 17 toabout 353, inclusive of FIG. 232 (SEQ ID NO:397), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1788 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e. transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from amino acidposition 1 through about amino acid position 16 in the sequence of FIG.232 (SEQ ID NO:397). Transmembrane domains have been tentativelyidentified as extending from about amino acid position 215 through aboutamino acid position 232 and about amino acid position 287 through aboutamino acid position 304 in the PRO1788 amino acid sequence (FIG. 232,SEQ ID NO:397).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 17to about 353, inclusive of FIG. 232 (SEQ ID NO:397), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1788 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1788polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1788 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 17 to 353 of FIG. 232 (SEQ ID NO:397).

In another aspect, the invention concerns an isolated PRO1788polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues17 to about 353, inclusive of FIG. 232 (SEQ ID NO:397).

In a further aspect, the invention concerns an isolated PRO1788polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 17 to353 of FIG. 232 (SEQ ID NO:397).

In yet another aspect, the invention concerns an isolated PRO1788polypeptide, comprising the sequence of amino acid residues 17 to about353, inclusive of FIG. 232 (SEQ ID NO:397), or a fragment thereofsufficient to provide a binding site for an anti-PRO1788 antibody.Preferably, the PRO1788 fragment retains a qualitative biologicalactivity of a native PRO1788 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1788 polypeptide having the sequence ofamino acid residues from about 17 to about 353, inclusive of FIG. 232(SEQ ID NO:397), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1788 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1788 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1788 polypeptide, by contactingthe native PRO1788 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1788 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

117. PRO1801

A cDNA clone (DNA83500-2506) has been identified, having homology tonucleic acid encoding IL-19 polypeptide, that encodes a novelpolypeptide, designated in the present application as “PRO1801”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1801 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1801 polypeptide having the sequence of amino acidresidues from about 1 or about 43 to about 261, inclusive of FIG. 234(SEQ ID NO:402), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1801 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 109 orabout 235 and about 891, inclusive, of FIG. 233 (SEQ ID NO:401).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203391(DNA83500-2506) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203391 (DNA83500-2506).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 43 to about 261, inclusive of FIG. 234 (SEQ IDNO:402), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 30 nucleotides, usually at least about 50nucleotides, more usually at least about 100 nucleotides and generallyat least about 150 nucleotides and produced by hybridizing a test DNAmolecule under stringent conditions with (a) a DNA molecule encoding aPRO1801 polypeptide having the sequence of amino acid residues from 1 orabout 43 to about 261, inclusive of FIG. 234 (SEQ ID NO:402), or (b) thecomplement of the DNA molecule of (a), and, if the DNA molecule has atleast about an 80% sequence identity, preferably at least about an 85%sequence identity, more preferably at least about a 90% sequenceidentity, most preferably at least about a 95% sequence identity to (a)or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1801 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 42 in the sequence of FIG. 234(SEQ ID NO:402).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 43 to about 261, inclusive of FIG. 234 (SEQ ID NO:402), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1801 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 233 (SEQ ID NO:401).

In another embodiment, the invention provides isolated PRO1801polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1801 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 43 to about 261 of FIG. 234(SEQ ID NO:402).

In another aspect, the invention concerns an isolated PRO1801polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 43 to about 261, inclusive of FIG. 234 (SEQ ID NO:402).

In a further aspect, the invention concerns an isolated PRO1801polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 43 to about 261, inclusive of FIG. 234 (SEQ ID NO:402).

In yet another aspect, the invention concerns an isolated PRO1801polypeptide, comprising the sequence of amino acid residues 1 or about43 to about 261, inclusive of FIG. 234 (SEQ ID NO:402), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1801antibody. Preferably, the PRO1801 fragment retains a qualitativebiological activity of a native PRO1801 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1801 polypeptide having the sequence ofamino acid residues from about 1 or about 43 to about 261, inclusive ofFIG. 234 (SEQ ID NO:402), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1801 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1801 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1801 polypeptide by contactingthe native PRO1801 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1501 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

Another embodiment of the present invention is directed to a method ofinhibiting the production of an inflammatory cytokine by a cell capableof producing that inflammatory cytokine, wherein the method comprisesthe step of contacting the cell with a PRO1801 polypeptide, wherein theproduction of the inflammatory cytokine is inhibited. The cell may be,for example, a T-cell, an NK cell or a macrophage and the inflammatorycytokine whose production is inhibited may be, for example, IL-1, IL-6,IFN-γ or TNF-α.

A further embodiment of the present invention is directed to a methodfor the treatment of an individual in need of immunosuppression, whereinthe method comprises the step of administering to the individual animmunosuppressive amount of a PRO1801 polypeptide. The individual inneed of immunosuppression may suffer from an autoimmune disease, such asrheumatoid arthritis, myasthenia gravis, insulin-dependent diabetesmellitus, systemic lupus erythematosus, thyroiditis or colitis, or fromseptic shock, endotoxic shock or any other type of disorder whereimmunosuppression is desired. The individual may also be one who hasreceived or is to receive a tissue transplant, where the method servesto inhibit rejection of the tissue transplant.

Other embodiments will become evident upon a reading of the presentspecification.

118. UCP4

A cDNA clone (DNA77568-1626) has been identified, having certainhomologies to some known human uncoupling proteins, that encodes a novelpolypeptide, designated in the present application as “UCP4.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a UCP4 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a UCP4 polypeptide having the sequence of amino acid residuesfrom about 1 to about 323, inclusive of FIG. 236 (SEQ ID NO:406), or (b)the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a UCP4 polypeptide comprising DNA hybridizing to thecomplement of the nucleic acid between about nucleotides 40 and about1011 inclusive, of FIG. 235 (SEQ ID NO:405). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a her aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No.203134, or (b) the complement of the DNA molecule of (a). In a preferredembodiment, the nucleic acid comprises a DNA encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No.203134. In a still further aspect, the invention concerns an isolatednucleic acid molecule comprising (a) DNA encoding a polypeptide havingat least about 80% sequence identity, preferably at least about 85%sequence identity, more preferably at least about 90% sequence identity,most preferably at least about 95% sequence identity to the sequence ofamino acid residues from about 1 to about 323, inclusive of FIG. 236(SEQ ID NO:406), or the complement of the DNA of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 323, inclusive of FIG. 236 (SEQ ID NO:406), or (b) thecomplement of the DNA of (a).

Further embodiments of the invention are directed to fragments of theUCP4 coding sequence, which are sufficiently long to be used ashybridization probes. Preferably, such fragments contain at least about20 to about 80 consecutive bases included in the sequence of FIG. 235(SEQ ID NO:405). Optionally, such fragments include the N-terminus orthe C-terminus of the sequence of FIG. 236 (SEQ ID NO:406).

In another embodiment, the invention provides isolated UCP4 polypeptideencoded by any of the isolated nucleic acid sequences hereinabovedefined.

In a specific aspect, the invention provides isolated native sequenceUCP4 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 323 of FIG. 236 (SEQ ID NO:406).

In another aspect, the invention concerns an isolated UCP4 polypeptide,comprising an amino acid sequence having at least about 80% sequenceidentity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 323, inclusive of FIG. 236 (SEQ ID NO:406).

In a further aspect, the invention concerns an isolated UCP4polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 to323 of FIG. 236 (SEQ ID NO:406).

In yet another aspect, the invention concerns an isolated UCP4polypeptide, comprising the sequence of amino acid residues 1 to about323, inclusive of FIG. 236 (SEQ ID NO:406), or a fragment thereofsufficient to, for instance, provide a binding site for an anti-UCP4antibody. Preferably, the UCP4 fragment retains at least one biologicalactivity of a native UCP4 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a UCP4 polypeptide having the sequence ofamino acid residues from about 1 to about 323, inclusive of FIG. 236(SEQ ID NO:406), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of the native UCP4 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-UCP4 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native UCP4 polypeptide, by contacting thenative UCP4 polypeptide with a candidate molecule and monitoring thedesired activity. The invention also provides therapeutic methods anddiagnostic methods using UCP4.

In a still further embodiment, the invention concerns a compositioncomprising a UCP4 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a carrier.

119. PRO193

A cDNA clone (DNA23322-1393) has been identified that encodes a novelmulti-transmembrane polypeptide, designated in the present applicationas “PRO193.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO193 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO193 polypeptide having the sequence of amino acid residuesfrom about 1 to about 158, inclusive of FIG. 238 (SEQ ID NO:410), or (b)the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO193 polypeptide comprising DNA hybridizing to thecomplement of the nucleic acid between about residues 138 and about 611,inclusive, of FIG. 237 (SEQ ID NO:409). Preferably, hybridization occursunder stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the sane maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203400(DNA23322-1393), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203400 (DNA23322-1393).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 1 to about 158, inclusive of FIG. 238 (SEQ IDNO:410), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule produced by hybridizing a test DNA molecule under stringentconditions with (a) a DNA molecule encoding a PRO193 polypeptide havingthe sequence of amino acid residues from about 1 to about 158, inclusiveof FIG. 238 (SEQ ID NO:410), or (b) the complement of the DNA moleculeof (a), and, if the DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), isolating the testDNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO193 polypeptide in its solubleform, i.e. transmembrane domain deleted or inactivated variants, or iscomplementary to such encoding nucleic acid molecule. The transmembranedomain has been tentatively identified as extending from about aminoacid positions 23-42, 60-80, 97-117 and 128-148 in the PRO193 amino acidsequence (FIG. 238, SEQ ID NO:410).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1to about 158, inclusive of FIG. 238 (SEQ ID NO:410), or (b) thecomplement of the DNA of (a).

In another embodiment, the invention provides isolated PRO193polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO193 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 through 158 of FIG. 238 (SEQ ID NO:410).

In another aspect, the invention concerns an isolated PRO193polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 to about 158, inclusive of FIG. 238 (SEQ ID NO:410).

In a further aspect, the invention concerns an isolated PRO193polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1through 158 of FIG. 238 (SEQ ID NO:410).

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO193 polypeptide having the sequence ofamino acid residues from about 1 to about 158, inclusive of FIG. 238(SEQ ID NO:410), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of the a native PRO193 polypeptide. In a particularembodiment, the agonist or antagonist is an anti-PRO193 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO193 polypeptide, by contactingthe native PRO193 polypeptide with a candidate molecule and monitoring abiological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO193 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

120. PRO1130

A cDNA clone (DNA59814-1486) has been identified, having homology tonucleic acid encoding the human 2-19 protein that encodes a novelpolypeptide, designated in the present application as “PRO1130”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1130 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1130 polypeptide having the sequence of amino acidresidues from about 1 or about 16 to about 224, inclusive of FIG. 240(SEQ ID NO:415), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1130 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 312 orabout 357 and about 983, inclusive, of FIG. 239 (SEQ ID NO:414).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203359(DNAS9814-1486) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203359 (DNA59814-1486).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 16 to about 224, inclusive of FIG. 240 (SEQ IDNO:415), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 10 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1130 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 224, inclusive of FIG. 240 (SEQ IDNO:415), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1130 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from about amino acidposition 1 to about amino acid position 15 in the sequence of FIG. 240(SEQ ID NO:415).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 16 to about 224, inclusive of FIG. 240 (SEQ ID NO:415), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1130 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 239 (SEQ ID NO:414).

In another embodiment, the invention provides isolated PRO1130polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1130 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 16 to about 224 of FIG. 240(SEQ ID NO:415).

In another aspect, the invention concerns an isolated PRO1130polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 16 to about 224, inclusive of FIG. 240 (SEQ ID NO:415).

In a further aspect, the invention concerns an isolated PRO1130polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 16 to about 224, inclusive of FIG. 240 (SEQ ID NO:415).

In yet another aspect, the invention concerns an isolated PRO1130polypeptide, comprising the sequence of amino acid residues 1 or about16 to about 224, inclusive of FIG. 240 (SEQ ID NO:415), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1130antibody. Preferably, the PRO1130 fragment retains a qualitativebiological activity of a native PRO1130 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1130 polypeptide having the sequence ofamino acid residues from about 1 or about 16 to about 224, inclusive ofFIG. 240 (SEQ ID NO:415), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1130 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1130 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1130 polypeptide by contactingthe native PRO1130 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1130 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

121. PRO1335

A cDNA clone (DNA62812-1594) has been identified, having homology tonucleic acid encoding carbonic anhydrase that encodes a novelpolypeptide, designated in the present application as “PRO1335”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1335 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1335 polypeptide having the sequence of amino acidresidues from about 1 or about 16 to about 337, inclusive of FIG. 242(SEQ ID NO:423), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1335 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about nucleotides 271 orabout 316 and about 1281, inclusive, of FIG. 241 (SEQ ID NO:422).Preferably, hybridization occurs under stringent hybridization and washconditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203248(DNA62812-1594) or (b) the complement of the nucleic acid molecule of(a). In a preferred embodiment, the nucleic acid comprises a DNAencoding the same mature polypeptide encoded by the human protein cDNAin ATCC Deposit No. 203248 (DNA62812-1594).

In still a further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues 1 or about 16 to about 337, inclusive of FIG. 242 (SEQ IDNO:423), or (b) the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least 180 nucleotides and produced by hybridizing atest DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1335 polypeptide having the sequence of amino acidresidues from 1 or about 16 to about 337, inclusive of FIG. 242 (SEQ IDNO:423), or (b) the complement of the DNA molecule of (a), and, if theDNA molecule has at least about an 80% sequence identity, prefereably atleast about an 85% sequence identity, more preferably at least about a90% sequence identity, most preferably at least about a 95% sequenceidentity to (a) or (b), isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1335 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, and itssoluble, i.e., transmembrane domain deleted or inactivated variants, oris complementary to such encoding nucleic acid molecule. The signalpeptide has been tentatively identified as extending from about aminoacid position 1 to about amino acid position 15 in the sequence of FIG.242 (SEQ ID NO:423). The transmembrane domain has been tentativelyidentified as extending from about amino acid position 291 to aboutamino acid position 310 in the PRO1335 amino acid sequence (FIG. 242,SEQ ID NO:423).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 16 to about 337, inclusive of FIG. 242 (SEQ ID NO:423), or (b)the complement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1335 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length and mostpreferably from about 20 to about 40 nucleotides in length and may bederived from the nucleotide sequence shown in FIG. 241 (SEQ ID NO:422).

In another embodiment, the invention provides isolated PRO1335polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a specific aspect, the invention provides isolated native sequencePRO1335 polypeptide, which in certain embodiments, includes an aminoacid sequence comprising residues 1 or about 16 to about 337 of FIG. 242(SEQ ID NO:423).

In another aspect, the invention concerns an isolated PRO1335polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues1 or about 16 to about 337, inclusive of FIG. 242 (SEQ ID NO:423).

In a further aspect, the invention concerns an isolated PRO1335polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 1 orabout 16 to about 337, inclusive of FIG. 242 (SEQ ID NO:423).

In yet another aspect, the invention concerns an isolated PRO1335polypeptide, comprising the sequence of amino acid residues 1 or about16 to about 337, inclusive of FIG. 242 (SEQ ID NO:423), or a fragmentthereof sufficient to provide a binding site for an anti-PRO1335antibody. Preferably, the PRO1335 fragment retains a qualitativebiological activity of a native PRO1335 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1335 polypeptide having the sequence ofamino acid residues from about 1 or about 16 to about 337, inclusive ofFIG. 242 (SEQ ID NO:423), or (b) the complement of the DNA molecule of(a), and if the test DNA molecule has at least about an 80% sequenceidentity, preferably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), (ii) culturing a hostcell comprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO1335 polypeptide. In a particular embodiment,the agonist or antagonist is an anti-PRO1335 antibody.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists of a native PRO1335 polypeptide by contactingthe native PRO1335 polypeptide with a candidate molecule and monitoringa biological activity mediated by said polypeptide.

In a still further embodiment, the invention concerns a compositioncomprising a PRO1335 polypeptide, or an agonist or antagonist ashereinabove defined, in combination with a pharmaceutically acceptablecarrier.

122. PRO1329

A cDNA clone (DNA66660-1585) has been identified that encodes a novelpolypeptide designated in the present application as “PRO1329.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1329 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1329 polypeptide having the sequence of amino acidresidues from 1 or about 17 to about 209, inclusive of FIG. 244 (SEQ IDNO:429), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1329 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 138 and about716, inclusive, of FIG. 243 (SEQ ID NO:428). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203279(DNA66660-1585), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203219 (DNA66660-1585).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 17 to about 209, inclusive of FIG. 244 (SEQ IDNO:429), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1329polypeptide having the sequence of amino acid residues from about 17 toabout 209, inclusive of FIG. 244 (SEQ ID NO:429), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1329 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 16 in the sequence of FIG. 244 (SEQ IDNO:429).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 17to about 209, inclusive of FIG. 244 (SEQ ID NO:429), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1329 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1329polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1329 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 17 to 209 of FIG. 244 (SEQ ID NO:429).

In another aspect, the invention concerns an isolated PRO1329polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues17 to about 209, inclusive of FIG. 244 (SEQ ID NO:429).

In a further aspect, the invention concerns an isolated PRO1329polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 17 to209 of FIG. 244 (SEQ ID NO:429).

In yet another aspect, the invention concerns an isolated PRO1329polypeptide, comprising the sequence of amino acid residues 17 to about209, inclusive of FIG. 244 (SEQ ID NO:429), or a fragment thereofsufficient to provide a binding site for an anti-PRO1329 antibody.Preferably, the PRO1329 fragment retains a qualitative biologicalactivity of a native PRO1329 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1329 polypeptide having the sequence ofamino acid residues from about 17 to about 209, inclusive of FIG. 244(SEQ ID NO:429), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

123. PRO1550

A cDNA clone (DNA76393-1664) has been identified that encodes a novelsecreted polypeptide and designated in the present application as“PRO1550.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1550 polypeptide.

In one aspect, the isolated nucleic acid comprises DNA having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to (a) a DNA moleculeencoding a PRO1550 polypeptide having the sequence of amino acidresidues from 1 or about 31 to about 243, inclusive of FIG. 246 (SEQ IDNO:431), or (b) the complement of the DNA molecule of (a).

In another aspect, the invention concerns an isolated nucleic acidmolecule encoding a PRO1550 polypeptide comprising DNA hybridizing tothe complement of the nucleic acid between about residues 228 and about866, inclusive, of FIG. 245 (SEQ ID NO:430). Preferably, hybridizationoccurs under stringent hybridization and wash conditions.

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity,preferably at least about 85% sequence identity, more preferably atleast about 90% sequence identity, most preferably at least about 95%sequence identity to (a) a DNA molecule encoding the same maturepolypeptide encoded by the human protein cDNA in ATCC Deposit No. 203323(DNA76393-1664), or (b) the complement of the DNA molecule of (a). In apreferred embodiment, the nucleic acid comprises a DNA encoding the samemature polypeptide encoded by the human protein cDNA in ATCC Deposit No.203323 (DNA76393-1664).

In a still further aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide having at leastabout 80% sequence identity, preferably at least about 85% sequenceidentity, more preferably at least about 90% sequence identity, mostpreferably at least about 95% sequence identity to the sequence of aminoacid residues from about 31 to about 243, inclusive of FIG. 246 (SEQ IDNO:431), or the complement of the DNA of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule having at least about 50 nucleotides, and preferably at leastabout 100 nucleotides and produced by hybridizing a test DNA moleculeunder stringent conditions with (a) a DNA molecule encoding a PRO1550polypeptide having the sequence of amino acid residues from about 31 toabout 243, inclusive of FIG. 246 (SEQ ID NO:431), or (b) the complementof the DNA molecule of (a), and, if the DNA molecule has at least aboutan 80% sequence identity, preferably at least about an 85% sequenceidentity, more preferably at least about a 90% sequence identity, mostpreferably at least about a 95% sequence identity to (a) or (b),isolating the test DNA molecule.

In a specific aspect, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO1550 polypeptide, with or withoutthe N-terminal signal sequence and/or the initiating methionine, or iscomplementary to such encoding nucleic acid molecule. The signal peptidehas been tentatively identified as extending from amino acid position 1through about amino acid position 30 in the sequence of FIG. 246 (SEQ IDNO:431).

In another aspect, the invention concerns an isolated nucleic acidmolecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 31to about 243, inclusive of FIG. 246 (SEQ ID NO:431), or (b) thecomplement of the DNA of (a).

Another embodiment is directed to fragments of a PRO1550 polypeptidecoding sequence that may find use as hybridization probes. Such nucleicacid fragments are from about 20 to about 80 nucleotides in length,preferably from about 20 to about 60 nucleotides in length, morepreferably from about 20 to about 50 nucleotides in length, and mostpreferably from about 20 to about 40 nucleotides in length.

In another embodiment, the invention provides isolated PRO1550polypeptide encoded by any of the isolated nucleic acid sequenceshereinabove defined.

In a specific aspect, the invention provides isolated native sequencePRO1550 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 31 to 243 of FIG. 246 (SEQ ID NO:431).

In another aspect, the invention concerns an isolated PRO1550polypeptide, comprising an amino acid sequence having at least about 80%sequence identity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to the sequence of amino acid residues31 to about 243, inclusive of FIG. 246 (SEQ ID NO:431).

In a further aspect, the invention concerns an isolated PRO1550polypeptide, comprising an amino acid sequence scoring at least about80% positives, preferably at least about 85% positives, more preferablyat least about 90% positives, most preferably at least about 95%positives when compared with the amino acid sequence of residues 31 to243 of FIG. 246 (SEQ ID NO:431).

In yet another aspect, the invention concerns an isolated PRO1550polypeptide, comprising the sequence of amino acid residues 31 to about243, inclusive of FIG. 246 (SEQ ID NO:431), or a fragment thereofsufficient to provide a binding site for an anti-PRO550 antibody.Preferably, the PRO1550 fragment retains a qualitative biologicalactivity of a native PRO1550 polypeptide.

In a still further aspect, the invention provides a polypeptide producedby (i) hybridizing a test DNA molecule under stringent conditions with(a) a DNA molecule encoding a PRO1550 polypeptide having the sequence ofamino acid residues from about 31 to about 243, inclusive of FIG. 246(SEQ ID NO:431), or (b) the complement of the DNA molecule of (a), andif the test DNA molecule has at least about an 80% sequence identity,preferably at least about an 85% sequence identity, more preferably atleast about a 90% sequence identity, most preferably at least about a95% sequence identity to (a) or (b), (ii) culturing a host cellcomprising the test DNA molecule under conditions suitable forexpression of the polypeptide, and (iii) recovering the polypeptide fromthe cell culture.

124. Additional Embodiments

In other embodiments of the present invention, the invention providesvectors comprising DNA encoding any of the herein describedpolypeptides. Host cell comprising any such vector are also provided. Byway of example, the host cells may be CHO cells, E. coli, or yeast. Aprocess for producing any of the herein described polypeptides isfurther provided and comprises culturing host cells under conditionssuitable for expression of the desired polypeptide and recovering thedesired polypeptide from the cell culture.

In other embodiments, the invention provides chimeric moleculescomprising any of the herein described polypeptides fused to aheterologous polypeptide or amino acid sequence. Example of suchchimeric molecules comprise any of the herein described polypeptidesfused to an epitope tag sequence or a Fc region of an immunoglobulin.

In another embodiment, the invention provides an antibody whichspecifically binds to any of the above or below described polypeptides.Optionally, the antibody is a monoclonal antibody, humanized antibody,antibody fragment or single-chain antibody.

In yet other embodiments, the invention provides oligonucleotide probesuseful for isolating genomic and cDNA nucleotide sequences, whereinthose probes may be derived from any of the above or below describednucleotide sequences.

In other embodiments, the invention provides an isolated nucleic acidmolecule comprising a nucleotide sequence that encodes a PROpolypeptide.

In one aspect, the isolated nucleic acid molecule comprises a nucleotidesequence having at least about 80% sequence identity, preferably atleast about 81% sequence identity, more preferably at least about 82%sequence identity, yet more preferably at least about 83% sequenceidentity, yet more preferably at least about 84% sequence identity, yetmore preferably at least about 85% sequence identity, yet morepreferably at least about 86% sequence identity, yet more preferably atleast about 87% sequence identity, yet more preferably at least about88% sequence identity, yet more preferably at least about 89% sequenceidentity, yet more preferably at least about 90% sequence identity, yetmore preferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet more preferably atleast about 93% sequence identity, yet more preferably at least about94% sequence identity, yet more preferably at least about 95% sequenceidentity, yet more preferably at least about 96% sequence identity, yetmore preferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet more preferablyat least about 99% sequence identity to (a) a DNA molecule encoding aPRO polypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein or an extracellular domain of a transmembrane protein, with orwithout the signal peptide, as disclosed herein, or (b) the complementof the DNA molecule of (a).

In other aspects, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% sequence identity,preferably at least about 81% sequence identity, more preferably atleast about 82% sequence identity, yet more preferably at least about83% sequence identity, yet more preferably at least about 84% sequenceidentity, yet more preferably at least about 85% sequence identity, yetmore preferably at least about 86% sequence identity, yet morepreferably at least about 87% sequence identity, yet more preferably atleast about 88% sequence identity, yet more preferably at least about89% sequence identity, yet more preferably at least about 90% sequenceidentity, yet more preferably at least about 91% sequence identity, yetmore preferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet more preferably atleast about 94% sequence identity, yet more preferably at least about95% sequence identity, yet more preferably at least about 96% sequenceidentity, yet more preferably at least about 97% sequence identity, yetmore preferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to (a) a DNA moleculecomprising the coding sequence of a full-length PRO polypeptide cDNA asdisclosed herein, the coding sequence of a PRO polypeptide lacking thesignal peptide as disclosed herein or the coding sequence of anextracellular domain of a transmembrane PRO polypeptide, with or withoutthe signal peptide, as disclosed herein, or (b) the complement of theDNA molecule of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising a nucleotide sequence having at least about 80%sequence identity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to (a) a DNAmolecule that encodes the same mature polypeptide encoded by any of thehuman protein cDNAs deposited with the ATCC as disclosed herein, or (b)the complement of the DNA molecule of (a).

Another aspect the invention provides an isolated nucleic acid moleculecomprising a nucleotide sequence encoding a PRO polypeptide which iseither transmembrane domain-deleted or transmembrane domain-inactivated,or is complementary to such encoding nucleotide sequence, wherein thetransmembrane domain(s) of such polypeptide are disclosed herein.Therefore, soluble extracellular domains of the herein described PROpolypeptides are contemplated.

Another embodiment is directed to fragments of a PRO polypeptide codingsequence that may find use as, for example, hybridization probes or forencoding fragments of a PRO polypeptide that may optionally encode apolypeptide comprising a binding site for an anti-PRO antibody. Suchnucleic acid fragments are usually at least about 20 nucleotides inlength, preferably at least about 30 nucleotides in length, morepreferably at least about 40 nucleotides in length, yet more preferablyat least about 50 nucleotides in length, yet more preferably at leastabout 60 nucleotides in length, yet more preferably at least about 70nucleotides in length, yet more preferably at least about 80 nucleotidesin length, yet more preferably at least about 90 nucleotides in length,yet more preferably at least about 100 nucleotides in length, yet morepreferably at least about 110 nucleotides in length, yet more preferablyat least about 120 nucleotides in length, yet more preferably at leastabout 130 nucleotides in length, yet more preferably at least about 140nucleotides in length, yet more preferably at least about 150nucleotides in length, yet more preferably at least about 160nucleotides in length, yet more preferably at least about 170nucleotides in length, yet more preferably at least about 180nucleotides in length, yet more preferably at least about 190nucleotides in length, yet more preferably at least about 200nucleotides in length, yet more preferably at least about 250nucleotides in length, yet more preferably at least about 300nucleotides in length, yet more preferably at least about 350nucleotides in length, yet more preferably at least about 400nucleotides in length, yet more preferably at least about 450nucleotides in length, yet more preferably at least about 500nucleotides in length, yet more preferably at least about 600nucleotides in length, yet more preferably at least about 700nucleotides in length, yet more preferably at least about 800nucleotides in length, yet more preferably at least about 900nucleotides in length and yet more preferably at least about 1000nucleotides in length, wherein in this context the term “about” meansthe referenced nucleotide sequence length plus or minus 10% of thatreferenced length. It is noted that novel fragments of a PROpolypeptide-encoding nucleotide sequence may be determined in a routinemanner by aligning the PRO polypeptide-encoding nucleotide sequence withother known nucleotide sequences using any of a number of well knownsequence alignment programs and determining which PROpolypeptide-encoding nucleotide sequence fragment(s) are novel. All ofsuch PRO polypeptide-encoding nucleotide sequences are contemplatedherein. Also contemplated are the PRO polypeptide fragments encoded bythese nucleotide molecule fragments, preferably those PRO polypeptidefragments that comprise a binding site for an anti-PRO antibody.

In another embodiment, the invention provides isolated PRO polypeptideencoded by any of the isolated nucleic acid sequences hereinaboveidentified.

In a certain aspect, the invention concerns an isolated PRO polypeptide,comprising an amino acid sequence having at least about 80% sequenceidentity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to a PROpolypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein or an extracellular domain of a transmembrane protein, with orwithout the signal peptide, as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptidecomprising an amino acid sequence having at least about 80% sequenceidentity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to an aminoacid sequence encoded by any of the human protein cDNAs deposited withthe ATCC as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptidecomprising an amino acid sequence scoring at least about 80% positives,preferably at least about 81% positives, more preferably at least about82% positives, yet more preferably at least about 83% positives, yetmore preferably at least about 84% positives, yet more preferably atleast about 85% positives, yet more preferably at least about 86%positives, yet more preferably at least about 87% positives, yet morepreferably at least about 88% positives, yet more preferably at leastabout 89% positives, yet more preferably at least about 90% positives,yet more preferably at least about 91% positives, yet more preferably atleast about 92% positives, yet more preferably at least about 93%positives, yet more preferably at least about 94% positives, yet morepreferably at least about 95% positives, yet more preferably at leastabout 96% positives, yet more preferably at least about 97% positives,yet more preferably at least about 98% positives and yet more preferablyat least about 99% positives when compared with the amino acid sequenceof a PRO polypeptide having a full-length amino acid sequence asdisclosed herein, an amino acid sequence lacking the signal peptide asdisclosed herein or an extracellular domain of a transmembrane protein,with or without the signal peptide, as disclosed herein.

In a specific aspect, the invention provides an isolated PRO polypeptidewithout the N-terminal signal sequence and/or the initiating methionineand is encoded by a nucleotide sequence that encodes such an amino acidsequence as hereinbefore described. Processes for producing the same arealso herein described, wherein those processes comprise culturing a hostcell comprising a vector which comprises the appropriate encodingnucleic acid molecule under conditions suitable for expression of thePRO polypeptide and recovering the PRO polypeptide from the cellculture.

Another aspect the invention provides an isolated PRO polypeptide whichis either transmembrane domain-deleted or transmembranedomain-inactivated. Processes for producing the same are also hereindescribed, wherein those processes comprise culturing a host cellcomprising a vector which comprises the appropriate encoding nucleicacid molecule under conditions suitable for expression of the PROpolypeptide and recovering the PRO polypeptide from the cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO polypeptide as defined herein. In aparticular embodiment, the agonist or antagonist is an anti-PRO antibodyor a small molecule.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists to a PRO polypeptide which comprise contactingthe PRO polypeptide with a candidate molecule and monitoring abiological activity mediated by said PRO polypeptide. Preferably, thePRO polypeptide is a native PRO polypeptide.

In a still further embodiment, the invention concerns a composition ofmatter comprising a PRO polypeptide, or an agonist or antagonist of aPRO polypeptide as herein described, or an anti-PRO antibody, incombination with a carrier. Optionally, the carrier is apharmaceutically acceptable carrier.

Another embodiment of the present invention is directed to the use of aPRO polypeptide, or an agonist or antagonist thereof as hereinbeforedescribed, or an anti-PRO antibody, for the preparation of a medicamentuseful in the treatment of a condition which is responsive to the PROpolypeptide, an agonist or antagonist thereof or an anti-PRO antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a nucleotide sequence (SEQ ID NO:3) of a native sequencePRO1560 (UNQ767) cDNA, wherein SEQ ID NO:3 is a clone designated hereinas “DNA 19902-1669”. The start and stop codons are shown in bold andunderlined font.

FIG. 2 shows the amino acid sequence (SEQ ID NO:4) derived from thecoding sequence of SEQ ID NO:3 shown in FIG. 1.

FIG. 3 shows a nucleotide sequence (SEQ ID NO:5) of a native sequencePRO444 (UNQ328) cDNA, wherein SEQ ID NO:5 is a clone designated hereinas “DNA26846-1397”. The start and stop codons are shown in bold andunderlined font.

FIG. 4 shows the amino acid sequence (SEQ ID NO:6) derived from thecoding sequence of SEQ ID NO:5 shown in FIG. 3.

FIG. 5 shows a nucleotide sequence (SEQ ID NO:7) of a native sequencePRO1018 (UNQ501) cDNA, wherein SEQ ID NO:7 is a clone designated hereinas “DNA56107-1415”. The start and stop codons are shown in bold andunderlined font.

FIG. 6 shows the amino acid sequence (SEQ ID NO:8) derived from thecoding sequence of SEQ ID NO:7 shown in FIG. 5.

FIG. 7 shows a nucleotide sequence (SEQ ID NO:9) of a native sequencePRO1773 (UNQ835) cDNA, wherein SEQ ID NO:9 is a clone designated hereinas “DNA56406-1704”. The start and stop codons are shown in bold andunderlined font.

FIG. 8 shows the amino acid sequence (SEQ ID NO:10) derived from thecoding sequence of SEQ ID NO:9 shown in FIG. 7.

FIG. 9 shows a nucleotide sequence (SEQ ID NO:11) of a native sequencePRO1477 (UNQ747) cDNA, wherein SEQ ID NO:11 is a clone designated hereinas “DNA56529-1647”. The start and stop codons are shown in bold andunderlined font.

FIG. 10 shows the amino acid sequence (SEQ ID NO:12) derived from thecoding sequence of SEQ ID NO:11 shown in FIG. 9.

FIG. 11 shows a nucleotide sequence (SEQ ID NO:16) of a native sequencePRO1478 (UNQ748) cDNA, wherein SEQ ID NO:16 is a clone designated hereinas “DNA56531-1648”. The start and stop codons are shown in bold andunderlined font.

FIG. 12 shows the amino acid sequence (SEQ ID NO:17) derived from thecoding sequence of SEQ ID NO:16 shown in FIG. 11.

FIG. 13 shows a nucleotide sequence (SEQ ID NO:21) of a native sequencePRO831 (UNQ471) cDNA, wherein SEQ ID NO:21 is a clone designated hereinas “DNA56862-1343”. The start and stop codons are shown in bold andunderlined font.

FIG. 14 shows the amino acid sequence (SEQ ID NO:22) derived from thecoding sequence of SEQ ID NO:21 shown in FIG. 13.

FIG. 15 shows a nucleotide sequence (SEQ ID NO:23) of a native sequencePRO1113 (UNQ556) cDNA, wherein SEQ ID NO:23 is a clone designated hereinas “DNA57254-1477”. The start and stop codons are shown in bold andunderlined font.

FIG. 16 shows the amino acid sequence (SEQ ID NO:24) derived from thecoding sequence of SEQ ID NO:23 shown in FIG. 15.

FIG. 17 shows a nucleotide sequence (SEQ ID NO:28) of a native sequencePRO1194 (UNQ607) cDNA, wherein SEQ ID NO:28 is a clone designated hereinas “DNA57841-1522”. The start and stop codons are shown in bold andunderlined font.

FIG. 18 shows the amino acid sequence (SEQ ID NO:29) derived from thecoding sequence of SEQ ID NO:28 shown in FIG. 17.

FIG. 19 shows a nucleotide sequence (SEQ ID NO:30) of a native sequencePRO1110 (UNQ553) cDNA, wherein SEQ ID NO:30 is a clone designated hereinas “DNA58727-1474”. The start and stop codons are shown in bold andunderlined font.

FIG. 20 shows the amino acid sequence (SEQ ID NO:31) derived from thecoding sequence of SEQ ID NO:30 shown in FIG. 19.

FIG. 21 shows a nucleotide sequence (SEQ ID NO:32) of a native sequencePRO1378 (UNQ715) cDNA, wherein SEQ ID NO:32 is a clone designated hereinas “DNA58730-1607”. The start and stop codons are shown in bold andunderlined font.

FIG. 22 shows the amino acid sequence (SEQ ID NO:33) derived from thecoding sequence of SEQ ID NO:32 shown in FIG. 21.

FIG. 23 shows a nucleotide sequence (SEQ ID NO:40) of a native sequencePRO1481 (UNQ750) cDNA, wherein SEQ ID NO:40 is a clone designated hereinas “DNA58732-1650”. The start and stop codons are shown in bold andunderlined font.

FIG. 24 shows the amino acid sequence (SEQ ID NO:41) derived from thecoding sequence of SEQ ID NO:40 shown in FIG. 23.

FIG. 25 shows a nucleotide sequence (SEQ ID NO:42) of a native sequencePRO1189 (UNQ603) cDNA, wherein SEQ ID NO:42 is a clone designated hereinas “DNA58828-1519”. The start and stop codons are shown in bold andunderlined font.

FIG. 26 shows the amino acid sequence (SEQ ID NO:43) derived from thecoding sequence of SEQ ID NO:42 shown in FIG. 25.

FIG. 27 shows a nucleotide sequence (SEQ ID NO:49) of a native sequencePRO1415 (UNQ731) cDNA, wherein SEQ ID NO:49 is a clone designated hereinas “DNA58852-1637”. The start and stop codons are shown in bold andunderlined font.

FIG. 28 shows the amino acid sequence (SEQ ID NO:50) derived from thecoding sequence of SEQ ID NO:49 shown in FIG. 27.

FIG. 29 shows a nucleotide sequence (SEQ ID NO:51) of a native sequencePRO1411 (UNQ729) cDNA, wherein SEQ ID NO:51 is a clone designated hereinas “DNA59212-1627”. The start and stop codons are shown in bold andunderlined font.

FIG. 30 shows the amino acid sequence (SEQ ID NO:52) derived from thecoding sequence of SEQ ID NO:51 shown in FIG. 29.

FIG. 31 shows a nucleotide sequence (SEQ ID NO:53) of a native sequencePRO1295 (UNQ664) cDNA, wherein SEQ ID NO:53 is a clone designated hereinas “DNA59218-1559”. The start and stop codons are shown in bold andunderlined font.

FIG. 32 shows the amino acid sequence (SEQ ID NO:54) derived from thecoding sequence of SEQ ID NO:53 shown in FIG. 31.

FIG. 33 shows a nucleotide sequence (SEQ ID NO:55) of a native sequencePRO1359 (UNQ708) cDNA, wherein SEQ ID NO:55 is a clone designated hereinas “DNA59219-1613”. The start and stop codons are shown in bold andunderlined font.

FIG. 34 shows the amino acid sequence (SEQ ID NO:56) derived from thecoding sequence of SEQ ID NO:55 shown in FIG. 33.

FIG. 35 shows a nucleotide sequence (SEQ ID NO:57) of a native sequencePRO1190 (UNQ604) cDNA, wherein SEQ ID NO:57 is a clone designated hereinas “DNA59586-1520”. The start and stop codons are shown in bold andunderlined font.

FIG. 36 shows the amino acid sequence (SEQ ID NO:58) derived from thecoding sequence of SEQ ID NO:57 shown in FIG. 35.

FIG. 37 shows a nucleotide sequence (SEQ ID NO:62) of a native sequencePRO1772 (UNQ834) cDNA, wherein SEQ ID NO:62 is a clone designated hereinas “DNA59817-1703”. The start and stop codons are shown in bold andunderlined font.

FIG. 38 shows the amino acid sequence (SEQ ID NO:63) derived from thecoding sequence of SEQ ID NO:62 shown in FIG. 37.

FIG. 39 shows a nucleotide sequence (SEQ ID NO:67) of a native sequencePRO1248 (UNQ631) cDNA, wherein SEQ ID NO:67 is a clone designated hereinas “DNA60278-1530”. The start and stop codons are shown in bold andunderlined font.

FIG. 40 shows the amino acid sequence (SEQ ID NO:68) derived from thecoding sequence of SEQ ID NO:67 shown in FIG. 39.

FIG. 41 shows a nucleotide sequence (SEQ ID NO:69) of a native sequencePRO1316 (UNQ682) cDNA, wherein SEQ ID NO:69 is a clone designated hereinas “DNA60608-1577”. The start and stop codons are shown in bold andunderlined font.

FIG. 42 shows the amino acid sequence (SEQ ID NO:70) derived from thecoding sequence of SEQ ID NO:69 shown in FIG. 41.

FIG. 43 shows a nucleotide sequence (SEQ ID NO:71) of a native sequencePRO1197 (UNQ610) cDNA, wherein SEQ ID NO:71 is a clone designated hereinas “DNA60611-1524”. The start and stop codons are shown in bold andunderlined font.

FIG. 44 shows the amino acid sequence (SEQ ID NO:72) derived from thecoding sequence of SEQ ID NO:71 shown in FIG. 43.

FIG. 45 shows a nucleotide sequence (SEQ ID NO:76) of a native sequencePRO1293 (UNQ662) cDNA, wherein SEQ ID NO:76 is a clone designated hereinas “DNA60618-1557”. The start and stop codons are shown in bold andunderlined font.

FIG. 46 shows the amino acid sequence (SEQ ID NO:77) derived from thecoding sequence of SEQ ID NO:76 shown in FIG. 45.

FIG. 47 shows a nucleotide sequence (SEQ ID NO:78) of a native sequencePRO1380 (UNQ717) cDNA, wherein SEQ ID NO:78 is a clone designated hereinas “DNA60740-1615”. The start and stop codons are shown in bold andunderlined font.

FIG. 48 shows the amino acid sequence (SEQ ID NO:79) derived from thecoding sequence of SEQ ID NO:78 shown in FIG. 47.

FIG. 49 shows a nucleotide sequence (SEQ ID NO:83) of a native sequencePRO1265 (UNQ636) cDNA, wherein SEQ ID NO:83 is a clone designated hereinas “DNA60764-1533”. The start and stop codons are shown in bold andunderlined font.

FIG. 50 shows the amino acid sequence (SEQ ID NO:84) derived from thecoding sequence of SEQ ID NO:83 shown in FIG. 49.

FIG. 51 shows a nucleotide sequence (SEQ ID NO:85) of a native sequencePRO1250 (UNQ633) cDNA, wherein SEQ ID NO:85 is a clone designated hereinas “DNA60775-1532”. The start and stop codons are shown in bold andunderlined font.

FIG. 52 shows the amino acid sequence (SEQ ID NO:86) derived from thecoding sequence of SEQ ID NO:85 shown in FIG. 51.

FIG. 53 shows a nucleotide sequence (SEQ ID NO:87) of a native sequencePRO1475 (UNQ746) cDNA, wherein SEQ ID NO:87 is a clone designated hereinas “DNA61185-1646”. The start and stop codons are shown in bold andunderlined font.

FIG. 54 shows the amino acid sequence (SEQ ID NO:88) derived from thecoding sequence of SEQ ID NO:87 shown in FIG. 53.

FIG. 55 shows a nucleotide sequence (SEQ ID NO:94) of a native sequencePRO1377 (UNQ714) cDNA, wherein SEQ ID NO:94 is a clone designated hereinas “DNA61608-1606”. The start and stop codons are shown in bold andunderlined font.

FIG. 56 shows the amino acid sequence (SEQ ID NO:95) derived from thecoding sequence of SEQ ID NO:94 shown in FIG. 55.

FIG. 57 shows a nucleotide sequence (SEQ ID NO:99) of a native sequencePRO1326 (UNQ686) cDNA, wherein SEQ ID NO:99 is a clone designated hereinas “DNA62808-1582”. The start and stop codons are shown in bold andunderlined font.

FIG. 58 shows the amino acid sequence (SEQ ID NO:100) derived from thecoding sequence of SEQ ID NO:99 shown in FIG. 57.

FIG. 59 shows a nucleotide sequence (SEQ ID NO:101) of a native sequencePRO1249 (UNQ632) cDNA, wherein SEQ ID NO:101 is a clone designatedherein as “DNA62809-1531”. The start and stop codons are shown in boldand underlined font.

FIG. 60 shows the amino acid sequence (SEQ ID NO:102) derived from thecoding sequence of SEQ ID NO:100 shown in FIG. 59.

FIG. 61 shows a nucleotide sequence (SEQ ID NO:103) of a native sequencePRO1315 (UNQ681) cDNA, wherein SEQ ID NO:103 is a clone designatedherein as “DNA62815-1578”. The start and stop codons are shown in boldand underlined font.

FIG. 62 shows the amino acid sequence (SEQ ID NO:104) derived from thecoding sequence of SEQ ID NO:103 shown in FIG. 61.

FIG. 63 shows a nucleotide sequence (SEQ ID NO:110) of a native sequencePRO1549 (UNQ782) cDNA, wherein SEQ ID NO:110 is a clone designatedherein as “DNA62845-1684”. The start and stop codons are shown in boldand underlined font.

FIG. 64 shows the amino acid sequence (SEQ ID NO:111) derived from thecoding sequence of SEQ ID NO:110 shown in FIG. 63.

FIG. 65 shows a nucleotide sequence (SEQ ID NO:115) of a native sequencePRO1430 (UNQ736) cDNA, wherein SEQ ID NO:115 is a clone designatedherein as “DNA64842-1632”. The start and stop codons are shown in boldand underlined font.

FIG. 66 shows the amino acid sequence (SEQ ID NO:116) derived from thecoding sequence of SEQ ID NO:115 shown in FIG. 65.

FIG. 67 shows a nucleotide sequence (SEQ ID NO:117) of a native sequencePRO1374 (UNQ711) cDNA, wherein SEQ ID NO:117 is a clone designatedherein as “DNA64849-1604”. The start and stop codons are shown in boldand underlined font.

FIG. 68 shows the amino acid sequence (SEQ ID NO:118) derived from thecoding sequence of SEQ ID NO:117 shown in FIG. 67.

FIG. 69 shows a nucleotide sequence (SEQ ID NO:122) of a native sequencePRO1311 (UNQ677) cDNA, wherein SEQ ID NO:122 is a clone designatedherein as “DNA64863-1573”. The start and stop codons are shown in boldand underlined font.

FIG. 70 shows the amino acid sequence (SEQ ID NO:123) derived from thecoding sequence of SEQ ID NO:122 shown in FIG. 69.

FIG. 71 shows a nucleotide sequence (SEQ ID NO:127) of a native sequencePRO1357 (UNQ706) cDNA, wherein SEQ ID NO:127 is a clone designatedherein as “DNA64881-1602”. The start and stop codons are shown in boldand underlined font.

FIG. 72 shows the amino acid sequence (SEQ ID NO:128) derived from thecoding sequence of SEQ ID NO:127 shown in FIG. 71.

FIG. 73 shows a nucleotide sequence (SEQ ID NO:129) of a native sequencePRO1244 (UNQ628) cDNA, wherein SEQ ID NO:129 is a clone designatedherein as “DNA64883-1526”. The start and stop codons are shown in boldand underlined font.

FIG. 74 shows the amino acid sequence (SEQ ID NO:130) derived from thecoding sequence of SEQ ID NO:129 shown in FIG. 73.

FIG. 75 shows a nucleotide sequence (SEQ ID NO:131) of a native sequencePRO1246 (UNQ630) cDNA, wherein SEQ ID NO:131 is a clone designatedherein as “DNA64885-1529”. The start and stop codons are shown in boldand underlined font.

FIG. 76 shows the amino acid sequence (SEQ ID NO:132) derived from thecoding sequence of SEQ ID NO:131 shown in FIG. 75.

FIG. 77 shows a nucleotide sequence (SEQ ID NO:133) of a native sequencePRO1356 (UNQ705) cDNA, wherein SEQ ID NO:133 is a clone designatedherein as “DNA64886-1601”. The start and stop codons are shown in boldand underlined font.

FIG. 78 shows the amino acid sequence (SEQ ID NO:134) derived from thecoding sequence of SEQ ID NO:133 shown in FIG. 77.

FIG. 79 shows a nucleotide sequence (SEQ ID NO:135) of a native sequencePRO1275 (UNQ645) cDNA, wherein SEQ ID NO:135 is a clone designatedherein as “DNA64888-1542”. The start and stop codons are shown in boldand underlined font.

FIG. 80 shows the amino acid sequence (SEQ ID NO:136) derived from thecoding sequence of SEQ ID NO:135 shown in FIG. 79.

FIG. 81 shows a nucleotide sequence (SEQ ID NO:137) of a native sequencePRO1274 (UNQ644) cDNA, wherein SEQ ID NO:137 is a clone designatedherein as “DNA64889-1542”. The start and stop codons are shown in boldand underlined font.

FIG. 82 shows the amino acid sequence (SEQ ID NO:138) derived from thecoding sequence of SEQ ID NO:137 shown in FIG. 81.

FIG. 83 shows a nucleotide sequence (SEQ ID NO:139) of a native sequencePRO1412 (UNQ730) cDNA, wherein SEQ ID NO:139 is a clone designatedherein as “DNA64897-1628”. The start and stop codons are shown in boldand underlined font.

FIG. 84 shows the amino acid sequence (SEQ ID NO:140) derived from thecoding sequence of SEQ ID NO:139 shown in FIG. 83.

FIG. 85 shows a nucleotide sequence (SEQ ID NO:141) of a native sequencePRO1557 (UNQ765) cDNA, wherein SEQ ID NO:141 is a clone designatedherein as “DNA64902-1667”. The start and stop codons are shown in boldand underlined font.

FIG. 86 shows the amino acid sequence (SEQ ID NO:142) derived from thecoding sequence of SEQ ID NO:141 shown in FIG. 85.

FIG. 87 shows a nucleotide sequence (SEQ ID NO:143) of a native sequencePRO1286 (UNQ655) cDNA, wherein SEQ ID NO:143 is a clone designatedherein as “DNA64903-1553”. The start and stop codons are shown in boldand underlined font.

FIG. 88 shows the amino acid sequence (SEQ ID NO:144) derived from thecoding sequence of SEQ ID NO:143 shown in FIG. 87.

FIG. 89 shows a nucleotide sequence (SEQ ID NO:145) of a native sequencePRO1294 (UN0663) cDNA, wherein SEQ ID NO:145 is a clone designatedherein as “DNA64905-1558”. The start and stop codons are shown in boldand underlined font.

FIG. 90 shows the amino acid sequence (SEQ ID NO:146) derived from thecoding sequence of SEQ ID NO:145 shown in FIG. 89.

FIG. 91 shows a nucleotide sequence (SEQ ID NO:147) of a native sequencePRO1347 (UNQ702) cDNA, wherein SEQ ID NO:147 is a clone designatedherein as “DNA64950-1590”. The start and stop codons are shown in boldand underlined font.

FIG. 92 shows the amino acid sequence (SEQ ID NO:148) derived from thecoding sequence of SEQ ID NO:147 shown in FIG. 91.

FIG. 93 shows a nucleotide sequence (SEQ ID NO:152) of a native sequencePRO1305 (UNQ671) cDNA, wherein SEQ ID NO:152 is a clone designatedherein as “DNA64952-1568”. The start and stop codons are shown in boldand underlined font.

FIG. 94 shows the amino acid sequence (SEQ ID NO:153) derived from thecoding sequence of SEQ ID NO:152 shown in FIG. 93.

FIG. 95 shows a nucleotide sequence (SEQ ID NO:157) of a native sequencePRO1273 (UNQ643) cDNA, wherein SEQ ID NO:157 is a clone designatedherein as “DNA65402-1540”. The start and stop codons are shown in boldand underlined font.

FIG. 96 shows the amino acid sequence (SEQ ID NO:158) derived from thecoding sequence of SEQ ID NO:157 shown in FIG. 95.

FIG. 97 shows a nucleotide sequence (SEQ ID NO:159) of a native sequencePRO1302 (UNQ668) cDNA, wherein SEQ ID NO:159 is a clone designatedherein as “DNA65403-1565”. The start and stop codons are shown in boldand underlined font.

FIG. 98 shows the amino acid sequence (SEQ ID NO:160) derived from thecoding sequence of SEQ ID NO:159 shown in FIG. 97.

FIG. 99 shows a nucleotide sequence (SEQ ID NO:161) of a native sequencePRO1283 (UNQ653) cDNA, wherein SEQ ID NO:161 is a clone designatedherein as “DNA65404-1551”. The start and stop codons are shown in boldand underlined font.

FIG. 100 shows the amino acid sequence (SEQ ID NO:162) derived from thecoding sequence of SEQ ID NO:161 shown in FIG. 99.

FIG. 101 shows a nucleotide sequence (SEQ ID NO:169) of a nativesequence PRO1279 (UNQ649) cDNA, wherein SEQ ID NO:169 is a clonedesignated herein as “DNA65405-1547”. The start and stop codons areshown in bold and underlined font.

FIG. 102 shows the amino acid sequence (SEQ ID NO:170) derived from thecoding sequence of SEQ ID NO:169 shown in FIG. 101.

FIG. 103 shows a nucleotide sequence (SEQ ID NO:179) of a nativesequence PRO1304 (UNQ670) cDNA, wherein SEQ ID NO:179 is a clonedesignated herein as “DNA65406-1567”. The start and stop codons areshown in bold and underlined font.

FIG. 104 shows the amino acid sequence (SEQ ID NO:180) derived from thecoding sequence of SEQ ID NO:179 shown in FIG. 103.

FIG. 105 shows a nucleotide sequence (SEQ ID NO:188) of a nativesequence PRO1317 (UNQ683) cDNA, wherein SEQ ID NO:188 is a clonedesignated herein as “DNA65408-1578”. The start and stop codons areshown in bold and underlined font.

FIG. 106 shows the amino acid sequence (SEQ ID NO:189) derived from thecoding sequence of SEQ ID NO:188 shown in FIG. 105.

FIG. 107 shows a nucleotide sequence (SEQ ID NO:193) of a nativesequence PRO1303 (UNQ669) cDNA, wherein SEQ ID NO:193 is a clonedesignated herein as “DNA65409-1566”. The start and stop codons areshown in bold and underlined font.

FIG. 108 shows the amino acid sequence (SEQ ID NO:194) derived from thecoding sequence of SEQ ID NO:193 shown in FIG. 107.

FIG. 109 shows a nucleotide sequence (SEQ ID NO:195) of a nativesequence PRO1306 (UNQ672) cDNA, wherein SEQ ID NO:195 is a clonedesignated herein as “DNA65410-1569”. The start and stop codons areshown in bold and underlined font.

FIG. 110 shows the amino acid sequence (SEQ ID NO:196) derived from thecoding sequence of SEQ ID NO:195 shown in FIG. 109.

FIGS. 111A-B show a nucleotide sequence (SEQ ID NO:197) of a nativesequence PRO1336 (UNQ691) cDNA, wherein SEQ ID NO:197 is a clonedesignated herein as “DNA65423-1595”. The start and stop codons areshown in bold and underlined font.

FIG. 112 shows the amino acid sequence (SEQ ID NO:198) derived from thecoding sequence of SEQ ID NO:198 shown in FIGS. 111A-B.

FIG. 113 shows a nucleotide sequence (SEQ ID NO:202) of a nativesequence PRO1278 (UNQ648) cDNA, wherein SEQ ID NO:202 is a clonedesignated herein as “DNA66304-1546”. The start and stop codons areshown in bold and underlined font.

FIG. 114 shows the amino acid sequence (SEQ ID NO:203) derived from thecoding sequence of SEQ ID NO:202 shown in FIG. 113.

FIG. 115 shows a nucleotide sequence (SEQ ID NO:209) of a nativesequence PRO1298 (UNQ666) cDNA, wherein SEQ ID NO:209 is a clonedesignated herein as “DNA66511-1563”. The start and stop codons areshown in bold and underlined font.

FIG. 116 shows the amino acid sequence (SEQ ID NO:210) derived from thecoding sequence of SEQ ID NO:209 shown in FIG. 115.

FIG. 117 shows a nucleotide sequence (SEQ ID NO:211) of a nativesequence PRO1301 (UNQ667) cDNA, wherein SEQ ID NO:211 is a clonedesignated herein as “DNA66512-1564”. The start and stop codons areshown in bold and underlined font.

FIG. 118 shows the amino acid sequence (SEQ ID NO:212) derived from thecoding sequence of SEQ ID NO:211 shown in FIG. 117.

FIG. 119 shows a nucleotide sequence (SEQ ID NO:213) of a nativesequence PRO1268 (UNQ638) cDNA, wherein SEQ ID NO:213 is a clonedesignated herein as “DNA66519-1535”. The start and stop codons areshown in bold and underlined font.

FIG. 120 shows the amino acid sequence (SEQ ID NO:214) derived from thecoding sequence of SEQ ID NO:213 shown in FIG. 119.

FIG. 121 shows a nucleotide sequence (SEQ ID NO:215) of a nativesequence PRO1269 (UNQ639) cDNA, wherein SEQ ID NO:215 is a clonedesignated herein as “DNA66520-1536”. The start and stop codons areshown in bold and underlined font.

FIG. 122 shows the amino acid sequence (SEQ ID NO:216) derived from thecoding sequence of SEQ ID NO:215 shown in FIG. 121.

FIG. 123 shows a nucleotide sequence (SEQ ID NO:217) of a nativesequence PRO1327 (UNQ687) cDNA, wherein SEQ ID NO:217 is a clonedesignated herein as “DNA66521-1583”. The start and stop codons areshown in bold and underlined font.

FIG. 124 shows the amino acid sequence (SEQ ID NO:218) derived from thecoding sequence of SEQ ID NO:217 shown in FIG. 123.

FIG. 125 shows a nucleotide sequence (SEQ ID NO:219) of a nativesequence PRO1382 (UNQ718) cDNA, wherein SEQ ID NO:219 is a clonedesignated herein as “DNA66526-1616”. The start and stop codons areshown in bold and underlined font.

FIG. 126 shows the amino acid sequence (SEQ ID NO:220) derived from thecoding sequence of SEQ ID NO:219 shown in FIG. 125.

FIG. 127 shows a nucleotide sequence (SEQ ID NO:224) of a nativesequence PRO1328 (UNQ688) cDNA, wherein SEQ ID NO:224 is a clonedesignated herein as “DNA66658-1584”. The start and stop codons areshown in bold and underlined font.

FIG. 128 shows the amino acid sequence (SEQ ID NO:225) derived from thecoding sequence of SEQ ID NO:224 shown in FIG. 127.

FIG. 129 shows a nucleotide sequence (SEQ ID NO:226) of a nativesequence PRO1325 (UNQ685) cDNA, wherein SEQ ID NO:226 is a clonedesignated herein as “DNA66659-1593”. The start and stop codons areshown in bold and underlined font.

FIG. 130 shows the amino acid sequence (SEQ ID NO:227) derived from thecoding sequence of SEQ ID NO:226 shown in FIG. 129.

FIG. 131 shows a nucleotide sequence (SEQ ID NO:228) of a nativesequence PRO1340 (UNQ695) cDNA, wherein SEQ ID NO:228 is a clonedesignated herein as “DNA66663-1598”. The start and stop codons areshown in bold and underlined font.

FIG. 132 shows the amino acid sequence (SEQ ID NO:229) derived from thecoding sequence of SEQ ID NO:228 shown in FIG. 131.

FIG. 133 shows a nucleotide sequence (SEQ ID NO:233) of a nativesequence PRO1339 (UNQ694) cDNA, wherein SEQ ID NO:233 is a clonedesignated herein as “DNA66669-1597”. The start and stop codons areshown in bold and underlined font.

FIG. 134 shows the amino acid sequence (SEQ ID NO:234) derived from thecoding sequence of SEQ ID NO:233 shown in FIG. 133.

FIG. 135 shows a nucleotide sequence (SEQ ID NO:235) of a nativesequence PRO1337 (UNQ692) cDNA, wherein SEQ ID NO:235 is a clonedesignated herein as “DNA66672-1586”. The start and stop codons areshown in bold and underlined font.

FIG. 136 shows the amino acid sequence (SEQ ID NO:236) derived from thecoding sequence of SEQ ID NO:235 shown in FIG. 135.

FIG. 137 shows a nucleotide sequence (SEQ ID NO:242) of a nativesequence PRO1342 (UNQ697) cDNA, wherein SEQ ID NO:242 is a clonedesignated herein as “DNA66674-1599”. The start and stop codons areshown in bold and underlined font.

FIG. 138 shows the amino acid sequence (SEQ ID NO:243) derived from thecoding sequence of SEQ ID NO:242 shown in FIG. 137.

FIG. 139 shows a nucleotide sequence (SEQ ID NO:247) of a nativesequence PRO1343 (UNQ698) cDNA, wherein SEQ ID NO:247 is a clonedesignated herein as “DNA66675-1587”. The start and stop codons areshown in bold and underlined font.

FIG. 140 shows the amino acid sequence (SEQ ID NO:248) derived from thecoding sequence of SEQ ID NO:247 shown in FIG. 139.

FIG. 141 shows a nucleotide sequence (SEQ ID NO:252) of a nativesequence PRO1480 (UNQ749) cDNA, wherein SEQ ID NO:252 is a clonedesignated herein as “DNA67962-1649”. The start and stop codons arcshown in bold and underlined font.

FIG. 142 shows the amino acid sequence (SEQ ID NO:253) derived from thecoding sequence of SEQ ID NO:252 shown in FIG. 141.

FIGS. 143A-B show a nucleotide sequence (SEQ ID NO:259) of a nativesequence PRO1487 (UNQ756) cDNA, wherein SEQ ID NO:259 is a clonedesignated herein as “DNA68836-1656”. The start and slop codons areshown in bold and underlined font.

FIG. 144 shows the amino acid sequence (SEQ ID NO:260) derived from thecoding sequence of SEQ ID NO:259 shown in FIGS. 143A-B.

FIGS. 145 shows a nucleotide sequence (SEQ ID NO:264) of a nativesequence PRO1418 (UNQ732) cDNA, wherein SEQ ID NO:264 is a clonedesignated herein as “DNA68864-1629”. The start and stop codons areshown in bold and underlined font.

FIG. 146 shows the amino acid sequence (SEQ ID NO:265) derived from thecoding sequence of SEQ ID NO:264 shown in FIG. 145.

FIG. 147 shows a nucleotide sequence (SEQ ID NO:266) of a nativesequence PRO1472 (UNQ744) cDNA, wherein SEQ ID NO:266 is a clonedesignated herein as “DNA68866-1644”. The start and stop codons areshown in bold and underlined font.

FIG. 148 shows the amino acid sequence (SEQ ID NO:267) derived from thecoding sequence of SEQ ID NO:266 shown in FIG. 147.

FIG. 149 shows a nucleotide sequence (SEQ ID NO:268) of a nativesequence PRO1461 (UNQ742) cDNA, wherein SEQ ID NO:268 is a clonedesignated herein as “DNA68871-1638”. The start and stop codons areshown in bold and underlined font.

FIG. 150 shows the amino acid sequence (SEQ ID NO:269) derived from thecoding sequence of SEQ ID NO:268 shown in FIG. 149.

FIG. 151 shows a nucleotide sequence (SEQ ID NO:270) of a nativesequence PRO1410 (UNQ728) cDNA, wherein SEQ ID NO:270 is a clonedesignated herein as “DNA68874-1622”. The start and stop codons areshown in bold and underlined font.

FIG. 152 shows the amino acid sequence (SEQ ID NO:271) derived from thecoding sequence of SEQ ID NO:270 shown in FIG. 151.

FIG. 153 shows a nucleotide sequence (SEQ ID NO:272) of a nativesequence PRO1568 (UNQ774) cDNA, wherein SEQ ID NO:272 is a clonedesignated herein as “DNA68880-1676”. The start and stop codons areshown in hold and underlined font.

FIG. 154 shows the amino acid sequence (SEQ ID NO:273) derived from thecoding sequence of SEQ ID NO:272 shown in FIG. 153.

FIG. 155 shows a nucleotide sequence (SEQ ID NO:274) of a nativesequence PRO1570 (UNQ776) cDNA, wherein SEQ ID NO:274 is a clonedesignated herein as “DNA68885-1678”. The start and stop codons areshown in bold and underlined font.

FIG. 156 shows the amino acid sequence (SEQ ID NO:275) derived from thecoding sequence of SEQ ID NO:274 shown in FIG. 155.

FIG. 157 shows a nucleotide sequence (SEQ ID NO:276) of a nativesequence PRO1317 (UNQ783) cDNA, wherein SEQ ID NO:276 is a clonedesignated herein as “DNA71166-1685”. The start and stop codons areshown in bold and underlined font.

FIG. 158 shows the amino acid sequence (SEQ ID NO:277) derived from thecoding sequence of SEQ ID NO:276 shown in FIG. 157.

FIG. 159 shows a nucleotide sequence (SEQ ID NO:281) of a nativesequence PRO1780 (UNQ842) cDNA, wherein SEQ ID NO:281 is a clonedesignated herein as “DNA71169-1709”. The start and stop codons areshown in bold and underlined font.

FIG. 160 shows the amino acid sequence (SEQ ID NO:282) derived from thecoding sequence of SEQ ID NO:281 shown in FIG. 159.

FIG. 161 shows a nucleotide sequence (SEQ ID NO:286) of a nativesequence PRO1486 (UNQ755) cDNA, wherein SEQ ID NO:286 is a clonedesignated herein as “DNA71180-1655”. The start and stop codons areshown in bold and underlined font.

FIG. 162 shows the amino acid sequence (SEQ ID NO:287) derived from thecoding sequence of SEQ ID NO:286 shown in FIG. 161.

FIG. 163 shows a nucleotide sequence (SEQ ID NO:291) of a nativesequence PRO1433 (UNQ738) cDNA, wherein SEQ ID NO:291 is a clonedesignated herein as “DNA71184-1634”. The start and stop codons areshown in bold and underlined font.

FIG. 164 shows the amino acid sequence (SEQ ID NO:292) derived front thecoding sequence of SEQ ID NO:291 shown in FIG. 163.

FIG. 165 shows a nucleotide sequence (SEQ ID NO:296) of a nativesequence PRO1490 (UNQ759) cDNA, wherein SEQ ID NO:296 is a clonedesignated herein as “DNA71213-1659”. The start and stop codons areshown in bold and underlined font.

FIG. 166 shows the amino acid sequence (SEQ ID NO:297) derived from thecoding sequence of SEQ ID NO:296 shown in FIG. 165.

FIG. 167 shows a nucleotide sequence (SEQ ID NO:301) of a nativesequence PRO1482 (UNQ751) cDNA, wherein SEQ ID NO:301 is a clonedesignated herein as “DNA71234-1651”. The start and stop codons areshown in bold and underlined font.

FIG. 168 shows the amino acid sequence (SEQ ID NO:302) derived from thecoding sequence of SEQ ID NO:301 shown in FIG. 167.

FIG. 169 shows a nucleotide sequence (SEQ ID NO:303) of a nativesequence PRO1446 (UNQ740) cDNA, wherein SEQ ID NO:303 is a clonedesignated herein as “DNA71277-1636”. The start and stop codons areshown in bold and underlined font.

FIG. 170 shows the amino acid sequence (SEQ ID NO:304) derived from thecoding sequence of SEQ ID NO:303 shown in FIG. 169.

FIG. 171 shows a nucleotide sequence (SEQ ID NO:305) of a nativesequence PRO1558 (UNQ766) cDNA, wherein SEQ ID NO:305 is a clonedesignated herein as “DNA71282-1668”. The start and stop codons areshown in bold and underlined font.

FIG. 172 shows the amino acid sequence (SEQ ID NO:306) derived from thecoding sequence of SEQ ID NO:305 shown in FIG. 171.

FIG. 173 shows a nucleotide sequence (SEQ ID NO:307) of a nativesequence PRO1604 (UNQ785) cDNA, wherein SEQ ID NO:307 is a clonedesignated herein as “DNA71286-1687”. The start and stop codons areshown in bold and underlined font.

FIG. 174 shows the amino acid sequence (SEQ ID NO:308) derived from thecoding sequence of SEQ ID NO:307 shown in FIG. 173.

FIG. 175 shows a nucleotide sequence (SEQ ID NO:309) of a nativesequence PRO1491 (UNQ760) cDNA, wherein SEQ ID NO:309 is a clonedesignated herein as “DNA71883-1660”. The start and stop codons areshown in bold and underlined font.

FIG. 176 shows the amino acid sequence (SEQ ID NO:310) derived from thecoding sequence of SEQ ID NO:309 shown in FIG. 175.

FIG. 177 shows a nucleotide sequence (SEQ ID NO:314) of a nativesequence PRO1431 (UNQ737) cDNA, wherein SEQ ID NO:314 is a clonedesignated herein as “DNA73401-1633”. The start and stop codons areshown in bold and underlined font.

FIG. 178 shows the amino acid sequence (SEQ ID NO:315) derived from thecoding sequence of SEQ ID NO:314 shown in FIG. 177.

FIGS. 179A-B show a nucleotide sequence (SEQ ID NO:316) of a nativesequence PRO1563 (UNQ769) cDNA, wherein SEQ ID NO:316 is a clonedesignated herein as “DNA73492-1671”. The start and stop codons areshown in bold and underlined font.

FIG. 180 shows the amino acid sequence (SEQ ID NO:317) derived from thecoding sequence of SEQ ID NO:316 shown in FIGS. 179A-B.

FIG. 181 shows a nucleotide sequence (SEQ ID NO:321) of a nativesequence PRO1565 (UNQ771) cDNA, wherein SEQ ID NO:321 is a clonedesignated herein as “DNA73727-1673”. The start and stop codons arcshown in bold and underlined font.

FIG. 182 shows the amino acid sequence (SEQ ID NO:322) derived from thecoding sequence of SEQ ID NO:321 shown in FIG. 181.

FIG. 183 shows a nucleotide sequence (SEQ ID NO:323) of a nativesequence PRO1571 (UNQ777) cDNA, wherein SEQ ID NO:323 is a clonedesignated herein as “DNA73730-1679”. The start and stop codons areshown in bold and underlined font.

FIG. 184 shows the amino acid sequence (SEQ ID NO:324) derived from thecoding sequence of SEQ ID NO:323 shown in FIG. 183.

FIG. 185 shows a nucleotide sequence (SEQ ID NO:325) of a nativesequence PRO1572 (UNQ778) cDNA, wherein SEQ ID NO:325 is a clonedesignated herein as “DNA73734-1680”. The start and stop codons areshown in bold and underlined font.

FIG. 186 shows the amino acid sequence (SEQ ID NO:326) derived from thecoding sequence of SEQ ID NO:325 shown in FIG. 185.

FIG. 187 shows a nucleotide sequence (SEQ ID NO:327) of a nativesequence PRO1573 (UNQ779) cDNA, wherein SEQ ID NO:327 is a clonedesignated herein as “DNA73735-1681”. The start and stop codons areshown in bold and underlined font.

FIG. 188 shows the amino acid sequence (SEQ ID NO:328) derived from thecoding sequence of SEQ ID NO:327 shown in FIG. 187.

FIG. 189 shows a nucleotide sequence (SEQ ID NO:329) of a nativesequence PRO1488 (UNQ757) cDNA, wherein SEQ ID NO:329 is a clonedesignated herein as “DNA73736-1657”. The start and stop codons areshown in bold and underlined font.

FIG. 190 shows the amino acid sequence (SEQ ID NO:330) derived from thecoding sequence of SEQ ID NO:329 shown in FIG. 189.

FIG. 191 shows a nucleotide sequence (SEQ ID NO:331) of a nativesequence PRO1489 (UNQ758) cDNA, wherein SEQ ID NO:331 is a clonedesignated herein as “DNA73737-1658”. The start and stop codons areshown in bold and underlined font.

FIG. 192 shows the amino acid sequence (SEQ ID NO:332) derived from thecoding sequence of SEQ ID NO:331 shown in FIG. 191.

FIG. 193 shows a nucleotide sequence (SEQ ID NO:333) of a nativesequence PRO1474 (UNQ745) cDNA, wherein SEQ ID NO:333 is a clonedesignated herein as “DNA73739-1645”. The start and stop codons areshown in bold and underlined font.

FIG. 194 shows the amino acid sequence (SEQ ID NO:334) derived from thecoding sequence of SEQ ID NO:333 shown in FIG. 193.

FIG. 195 shows a nucleotide sequence (SEQ ID NO:335) of a nativesequence PRO1508 (UNQ761) cDNA, wherein SEQ ID NO:335 is a clonedesignated herein as “DNA73742-1662”. The start and stop codons areshown in bold and underlined font.

FIG. 196 shows the amino acid sequence (SEQ ID NO:336) derived from thecoding sequence of SEQ ID NO:335 shown in FIG. 195.

FIG. 197 shows a nucleotide sequence (SEQ ID NO:337) of a nativesequence PRO1555 (UNQ763) cDNA, wherein SEQ ID NO:337 is a clonedesignated herein as “DNA73744-1665”. The start and stop codons areshown in bold and underlined font.

FIG. 198 shows the amino acid sequence (SEQ ID NO:338) derived from thecoding sequence of SEQ ID NO:337 shown in FIG. 197.

FIG. 199 shows a nucleotide sequence (SEQ ID NO:339) of a nativesequence PRO1485 (UNQ754) cDNA, wherein SEQ ID NO:339 is a clonedesignated herein as “DNA73746-1654”. The start and stop codons areshown in bold and underlined font.

FIG. 200 shows the amino acid sequence (SEQ ID NO:340) derived from thecoding sequence of SEQ ID NO:339 shown in FIG. 199.

FIG. 201 shows a nucleotide sequence (SEQ ID NO:346) of a nativesequence PRO1564 (UNQ770) cDNA, wherein SEQ ID NO:346 is a clonedesignated herein as “DNA73760-1672”. The start and stop codons areshown in bold and underlined font.

FIG. 202 shows the amino acid sequence (SEQ ID NO:347) derived from thecoding sequence of SEQ ID NO:346 shown in FIG. 201.

FIG. 203 shows a nucleotide sequence (SEQ ID NO:351) of a nativesequence PRO1755 (UNQ828) cDNA, wherein SEQ ID NO:351 is a clonedesignated herein as “DNA76396-1698”. The start and stop codons areshown in bold and underlined font.

FIG. 204 shows the amino acid sequence (SEQ ID NO:352) derived from thecoding sequence of SEQ ID NO:351 shown in FIG. 203.

FIG. 205 shows a nucleotide sequence (SEQ ID NO:353) of a nativesequence PRO1757 (UNQ830) cDNA, wherein SEQ ID NO:353 is a clonedesignated herein as “DNA76398-1699”. The start and stop codons areshown in bold and underlined font.

FIG. 206 shows the amino acid sequence (SEQ ID NO: 354) derived from thecoding sequence of SEQ ID NO:353 shown in FIG. 205.

FIG. 207 shows a nucleotide sequence (SEQ ID NO:355) of a nativesequence PRO1758 (UNQ831) cDNA, wherein SEQ ID NO:355 is a clonedesignated herein as “DNA76399-1700”. The start and stop codons areshown in bold and underlined font.

FIG. 208 shows the amino acid sequence (SEQ ID NO:356) derived from thecoding sequence of SEQ ID NO:355 shown in FIG. 207.

FIG. 209 shows a nucleotide sequence (SEQ ID NO:357) of a nativesequence PRO1575 (UNQ781) cDNA, wherein SEQ ID NO:357 is a clonedesignated herein as “DNA76401-1683”. The start and stop codons areshown in bold and underlined font.

FIG. 210 shows the amino acid sequence (SEQ ID NO:358) derived from thecoding sequence of SEQ ID NO:357 shown in FIG. 209.

FIG. 211 shows a nucleotide sequence (SEQ ID NO:363) of a nativesequence PRO1787 (UNQ849) cDNA, wherein SEQ ID NO:363 is a clonedesignated herein as “DNA76510-2504”. The start and stop codons areshown in bold and underlined font.

FIG. 212 shows the amino acid sequence (SEQ ID NO:364) derived from thecoding sequence of SEQ ID NO:363 shown in FIG. 211.

FIG. 213 shows a nucleotide sequence (SEQ ID NO:365) of a nativesequence PRO1781 (UNQS43) cDNA, wherein SEQ ID NO:365 is a clonedesignated herein as “DNA76522-2500”. The start and stop codons areshown in bold and underlined font.

FIG. 214 shows the amino acid sequence (SEQ ID NO:366) derived from thecoding sequence of SEQ ID NO:365 shown in FIG. 213.

FIG. 215 shows a nucleotide sequence (SEQ ID NO:371) of a nativesequence PRO1556 (UNQ764) cDNA, wherein SEQ ID NO:371 is a clonedesignated herein as “DNA76529-1666”. The start and stop codons areshown in bold and underlined font.

FIG. 216 shows the amino acid sequence (SEQ ID NO:372) derived from thecoding sequence of SEQ ID NO:371 shown in FIG. 215.

FIG. 217 shows a nucleotide sequence (SEQ ID NO:373) of a nativesequence PRO1759 (UNQ832) cDNA, wherein SEQ ID NO:373 is a clonedesignated herein as “DNA76531-1701”. The start and stop codons areshown in bold and underlined font.

FIG. 218 shows the amino acid sequence (SEQ ID NO:374) derived from thecoding sequence of SEQ ID NO:373 shown in FIG. 217.

FIG. 219 shows a nucleotide sequence (SEQ ID NO:375) of a nativesequence PRO1760 (UNQ833) cDNA, wherein SEQ ID NO:375 is a clonedesignated herein as “DNA76532-1702”. The start and stop codons areshown in bold and underlined font.

FIG. 220 shows the amino acid sequence (SEQ ID NO:376) derived from thecoding sequence of SEQ ID NO:375 shown in FIG. 219.

FIG. 221 shows a nucleotide sequence (SEQ ID NO:377) of a nativesequence PRO1561 (UNQ768) cDNA, wherein SEQ ID NO:377 is a clonedesignated herein as “DNA76538-1670”. The start and stop codons areshown in bold and underlined font.

FIG. 222 shows the amino acid sequence (SEQ ID NO:378) derived from thecoding sequence of SEQ ID NO:377 shown in FIG. 221.

FIG. 223 shows a nucleotide sequence (SEQ ID NO:382) of a nativesequence PRO1567 (UNQ773) cDNA, wherein SEQ ID NO:382 is a clonedesignated herein as “DNA76541-1675”. The start and stop codons areshown in bold and underlined font.

FIG. 224 shows the amino acid sequence (SEQ ID NO:383) derived from thecoding sequence of SEQ ID NO:382 shown in FIG. 223.

FIG. 225 shows a nucleotide sequence (SEQ ID NO:384) of a nativesequence PRO1693 (UNQ803) cDNA, wherein SEQ ID NO:384 is a clonedesignated herein as “DNA77301-1693”. The start and stop codons areshown in bold and underlined font.

FIG. 226 shows the amino acid sequence (SEQ ID NO:385) derived from thecoding sequence of SEQ ID NO:384 shown in FIG. 225.

FIG. 227 shows a nucleotide sequence (SEQ ID NO:389) of a nativesequence PRO1784 (UNQ846) cDNA, wherein SEQ ID NO:389 is a clonedesignated herein as “DNA77303-2502”. The start and stop codons areshown in bold and underlined font.

FIG. 228 shows the amino acid sequence (SEQ ID NO:390) derived from thecoding sequence of SEQ ID NO:389 shown in FIG. 227.

FIG. 229 shows a nucleotide sequence (SEQ ID NO:394) of a nativesequence PRO1605 (UNQ786) cDNA, wherein SEQ ID NO:394 is a clonedesignated herein as “DNA77648-1688”. The start and stop codons arcshown in bold and underlined font.

FIG. 230 shows the amino acid sequence (SEQ ID NO:395) derived from thecoding sequence of SEQ ID NO:394 shown in FIG. 229.

FIG. 231 shows a nucleotide sequence (SEQ ID NO:396) of a nativesequence PRO1788 (UNQ850) cDNA, wherein SEQ ID NO:396 is a clonedesignated herein as “DNA77652-2505”. The start and stop codons areshown in bold and underlined font.

FIG. 232 shows the amino acid sequence (SEQ ID NO:397) derived from thecoding sequence of SEQ ID NO:396 shown in FIG. 231.

FIG. 233 shows a nucleotide sequence (SEQ ID NO:401) of a nativesequence PRO1801 (UNQ852) cDNA, wherein SEQ ID NO:401 is a clonedesignated herein as “DNA83500-2506”. The start and stop codons areshown in bold and underlined font.

FIG. 234 shows the amino acid sequence (SEQ ID NO:402) derived from thecoding sequence of SEQ ID NO:401 shown in FIG. 233.

FIG. 235 shows a nucleotide sequence (SEQ ID NO:405) of a nativesequence UCP4 cDNA, wherein SEQ ID NO:405 is a clone designated hereinas “DNA77568-1626”. The start and stop codons are shown in bold andunderlined font.

FIG. 236 shows the amino acid sequence (SEQ ID NO:406) derived from thecoding sequence of SEQ ID NO:405 shown in FIG. 235.

FIG. 237 shows a nucleotide sequence (SEQ ID NO:409) of a nativesequence PRO193 cDNA, wherein SEQ ID NO:409 is a clone designated hereinas “DNA23322-1393”. The start and stop codons are shown in bold andunderlined font.

FIG. 238 shows the amino acid sequence (SEQ ID NO:410) derived from thecoding sequence of SEQ ID NO:409 shown in FIG. 237.

FIG. 239 shows a nucleotide sequence (SEQ ID NO:414) of a nativesequence PRO1130 cDNA, wherein SEQ ID NO:414 is a clone designatedherein as “DNA59814-1486”. The start and stop codons are shown in boldand underlined font.

FIG. 240 shows the amino acid sequence (SEQ ID NO:415) derived from thecoding sequence of SEQ ID NO:414 shown in FIG. 239.

FIG. 241 shows a nucleotide sequence (SEQ ID NO:422) of a nativesequence PRO1335 cDNA, wherein SEQ ID NO:422 is a clone designatedherein as “DNA62812-1594”. The start and stop codons are shown in boldand underlined font.

FIG. 242 shows the amino acid sequence (SEQ ID NO:423) derived from thecoding sequence of SEQ ID NO:422 shown in FIG. 241.

FIG. 243 shows a nucleotide sequence (SEQ ID NO:428) of a nativesequence PRO1329 cDNA, wherein SEQ ID NO:428 is a clone designatedherein as “DNA66660-1585”. The start and stop codons are shown in boldand underlined font.

FIG. 244 shows the amino acid sequence (SEQ ID NO:429) derived from thecoding sequence of SEQ ID NO:428 shown in FIG. 243.

FIG. 245 shows a nucleotide sequence (SEQ ID NO:430) of a nativesequence PRO1550 cDNA, wherein SEQ ID NO:430 is a clone designatedherein as “DNA76393-1664”. The start and stop codons are shown in boldand underlined font.

FIG. 246 shows the amino acid sequence (SEQ ID NO:431) derived from thecoding sequence of SEQ ID NO:430 shown in FIG. 245.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

The terms “PRO polypeptide” and “PRO” as used herein and whenimmediately followed by a numerical designation refer to variouspolypeptides, wherein the complete designation (i.e., PRO/number) refersto specific polypeptide sequences as described herein. The terms“PRO/number polypeptide” and “PRO/number” wherein the term “number” isprovided as an actual numerical designation as used herein encompassnative sequence polypeptides and polypeptide variants (which are furtherdefined herein). The PRO polypeptides described herein may be isolatedfrom a variety of sources, such as from human tissue types or fromanother source, or prepared by recombinant or synthetic methods.

A “native sequence PRO polypeptide” comprises a polypeptide having thesame amino acid sequence as the corresponding PRO polypeptide derivedfrom nature. Such native sequence PRO polypeptides can be isolated fromnature or can be produced by recombinant or synthetic means. The term“native sequence PRO polypeptide” specifically encompassesnaturally-occurring truncated or secreted forms of the specific PROpolypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively spliced forms)and naturally-occurring allelic variants of the polypeptide. In variousembodiments of the invention, the native sequence PRO polypeptidesdisclosed herein are mature or full-length native sequence polypeptidescomprising the full-length amino acids sequences shown in theaccompanying figures. Start and stop codons are shown in bold font andunderlined in the figures. However, while the PRO polypeptide disclosedin the accompanying figures arc shown to begin with methionine residuesdesignated herein as amino acid position 1 in the figures, it isconceivable and possible that other methionine residues located eitherupstream or downstream from the amino acid position 1 in the figures maybe employed as the starting amino acid residue for the PRO polypeptides.

The PRO polypeptide “extracellular domain” or “ECD” refers to a form ofthe PRO polypeptide which is essentially free of the transmembrane andcytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have lessthan 1% of such transmembrane and/or cytoplasmic domains and preferably,will have less than 0.5% of such domains. It will be understood that anytransmembrane domains identified for the PRO polypeptides of the presentinvention are identified pursuant to criteria routinely employed in theart for identifying that type of hydrophobic domain. The exactboundaries of a transmembrane domain may vary but most likely by no morethan about 5 amino acids at either end of the domain as initiallyidentified herein. Optionally, therefore, an extracellular domain of aPRO polypeptide may contain from about 5 or fewer amino acids on eitherside of the transmembrane domain/extracellular domain boundary asidentified in the Examples or specification and such polypeptides, withor without the associated signal peptide, and nucleic acid encodingthem, are comtemplated by the present invention.

The approximate location of the “signal peptides” of the various PROpolypeptides disclosed herein are shown in the present specificationand/or the accompanying figures. It is noted, however, that theC-terminal boundary of a signal peptide may vary, but most likely by nomore than about 5 amino acids on either side of the signal peptideC-terminal boundary as initially identified herein, wherein theC-terminal boundary of the signal peptide may be identified pursuant tocriteria routinely employed in the art for identifying that type ofamino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10: 1-6(1997) and von Heinje et al., Nucl. Acids. Res. 14: 4683-4690 (1986)).Moreover, it is also recognized that, in some cases, cleavage of asignal sequence from a secreted polypeptide is not entirely uniform,resulting in more than one secreted species. These mature polypeptides,where the signal peptide is cleaved within no more than about 5 aminoacids on either side of the C-terminal boundary of the signal peptide asidentified herein, and the polynucleotides encoding them, arecontemplated by the present invention.

“PRO polypeptide variant” means an active PRO polypeptide as definedabove or below having at least about 80% amino acid sequence identitywith a full-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any other fragment ofa full-length PRO polypeptide sequence as disclosed herein. Such PROpolypeptide variants include, for instance, PRO polypeptides wherein oneor more amino acid residues are added, or deleted, at the N- orC-terminus of the full-length native amino acid sequence. Ordinarily, aPRO polypeptide variant will have at least about 80% amino acid sequenceidentity, preferably at least about 81% amino acid sequence identity,more preferably at least about 82% amino acid sequence identity, morepreferably at least about 83% amino acid sequence identity, morepreferably at least about 84% amino acid sequence identity, morepreferably at least about 85% amino acid sequence identity, morepreferably at least about 86% amino acid sequence identity, morepreferably at least about 87% amino acid sequence identity, morepreferably at least about 88% amino acid sequence identity, morepreferably at least about 89% amino acid sequence identity, morepreferably at least about 90% amino acid sequence identity, morepreferably at least about 91% amino acid sequence identity, morepreferably at least about 92% amino acid sequence identity, morepreferably at least about 93% amino acid sequence identity, morepreferably at least about 94% amino acid sequence identity, morepreferably at least about 95% amino acid sequence identity, morepreferably at least about 96% amino acid sequence identity, morepreferably at least about 97% amino acid sequence identity, morepreferably at least about 98% amino acid sequence identity and mostpreferably at least about 99% amino acid sequence identity with afull-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any otherspecifically defined fragment of a full-length PRO polypeptide sequenceas disclosed herein. Ordinarily, PRO variant polypeptides are at leastabout 10 amino acids in length, often at least about 20 amino acids inlength, more often at least about 30 amino acids in length, more oftenat least about 40 amino acids in length, more often at least about 50amino acids in length, more often at least about 60 amino acids inlength, more often at least about 70 amino acids in length, more oftenat least about 80 amino acids in length, more often at least about 90amino acids in length, more often at least about 100 amino acids inlength, more often at least about 150 amino acids in length, more oftenat least about 200 amino acids in length, more often at least about 300amino acids in length, or more.

“Percent (%) amino acid sequence identity” with respect to the PROpolypeptide sequences identified herein is defined as the percentage ofamino acid residues in a candidate sequence that are identical with theamino acid residues in the specific PRO polypeptide sequence, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity, and not considering anyconservative substitutions as part of the sequence identity. Alignmentfor purposes of determining percent amino acid sequence identity can beachieved in various ways that are within the skill in the art, forinstance, using publicly available computer software such as BLAST,BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the artcan determine appropriate parameters for measuring alignment, includingany algorithms needed to achieve maximal alignment over the full lengthof the sequences being compared. For purposes herein, however, % aminoacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:100 times the fraction X/Ywhere X is the number of amino acid residues scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofA and B, and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence A isnot equal to the length of amino acid sequence B, the % amino acidsequence identity of A to B will not equal the % amino acid sequenceidentity of B to A. As examples of % amino acid sequence identitycalculations using this method, Tables 2 and 3 demonstrate how tocalculate the % amino acid sequence identity of the amino acid sequencedesignated “Comparison Protein” to the amino acid sequence designated“PRO”, wherein “PRO” represents the amino acid sequence of ahypothetical PRO polypeptide of interest, “Comparison Protein”represents the amino acid sequence of a polypeptide against which the“PRO” polypeptide of interest is being compared, and “X, “Y” and “Z”each represent different hypothetical amino acid residues.

Unless specifically stated otherwise, all % amino acid sequence identityvalues used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, % aminoacid sequence identity values may also be obtained as described below byusing the WU-BLAST-2 computer program (Altschul et al., Methods inEnzymology 266: 460-480 (1996)). Most of the WU-BLAST-2 searchparameters are set to the default values. Those not set to defaultvalues, i.e., the adjustable parameters, are set with the followingvalues: overlap span=1, overlap fraction=0.125, word threshold (T)=11,and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % amino acidsequence identity value is determined by dividing (a) the number ofmatching identical amino acid residues between the amino acid sequenceof the PRO polypeptide of interest having a sequence derived from thenative PRO polypeptide and the comparison amino acid sequence ofinterest (i.e., the sequence against which the PRO polypeptide ofinterest is being compared which may be a PRO variant polypeptide) asdetermined by WU-BLAST-2 by (b) the total number of amino acid residuesof the PRO polypeptide of interest. For example, in the statement “apolypeptide comprising an the amino acid sequence A which has or havingat least 80% amino acid sequence identity to the amino acid sequence B”,the amino acid sequence A is the comparison amino acid sequence ofinterest and the amino acid sequence B is the amino acid sequence of thePRO polypeptide of interest.

Percent amino acid sequence identity may also be determined using thesequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic AcidsRes. 25: 3389-3402 (1997)). The NCBI-BLAST2 sequence comparison programmay be downloaded from http://www.ncbi.nim.nih.gov. NCBI-BLAST2 usesseveral search parameters, wherein all of those search parameters areset to default values including, for example, unmask=yes, strand=all,expected occurrences=10, minimum low complexity length=15/5, multi-passe-value=0.01, constant for multi-pass=25, dropoff for final gappedalignment=25 and scoring matrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:100 times the fraction X/Ywhere X is the number of amino acid residues scored as identical matchesby the sequence alignment program NCBI-BLAST2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A.

“PRO variant polynucleotide” or “PRO variant nucleic acid sequence”means a nucleic acid molecule which encodes an active PRO polypeptide asdefined below and which has at least about 80% nucleic acid sequenceidentity with a nucleotide acid sequence encoding a full-length nativesequence PRO polypeptide sequence as disclosed herein, a full-lengthnative sequence PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any other fragment ofa full-length PRO polypeptide sequence as disclosed herein. Ordinarily,a PRO variant polynucleotide will have at least about 80% nucleic acidsequence identity, more preferably at least about 81% nucleic acidsequence identity, more preferably at least about 82% nucleic acidsequence identity, more preferably at least about 83% nucleic acidsequence identity, more preferably at least about 84% nucleic acidsequence identity, more preferably at least about 85% nucleic acidsequence identity, more preferably at least about 86% nucleic acidsequence identity, more preferably at least about 87% nucleic acidsequence identity, more preferably at least about 88% nucleic acidsequence identity, more preferably at least about 89% nucleic acidsequence identity, more preferably at least about 90% nucleic acidsequence identity, more preferably at least about 91% nucleic acidsequence identity, more preferably at least about 92% nucleic acidsequence identity, more preferably at least about 93% nucleic acidsequence identity, more preferably at least about 94% nucleic acidsequence identity, more preferably at least about 95% nucleic acidsequence identity, more preferably at least about 96% nucleic acidsequence identity, more preferably at least about 97% nucleic acidsequence identity, more preferably at least about 98% nucleic acidsequence identity and yet more preferably at least about 99% nucleicacid sequence identity with a nucleic acid sequence encoding afull-length native sequence PRO polypeptide sequence as disclosedherein, a full-length native sequence PRO polypeptide sequence lackingthe signal peptide as disclosed herein, an extracellular domain of a PROpolypeptide, with or without the signal sequence, as disclosed herein orany other fragment of a full-length PRO polypeptide sequence asdisclosed herein. Variants do not encompass the native nucleotidesequence.

Ordinarily, PRO variant polynucleotides are at least about 30nucleotides in length, often at least about 60 nucleotides in length,more often at least about 90 nucleotides in length, more often at leastabout 120 nucleotides in length, more often at least about 150nucleotides in length, more often at least about 180 nucleotides inlength, more often at least about 210 nucleotides in length, more oftenat least about 240 nucleotides in length, more often at least about 270nucleotides in length, more often at least about 300 nucleotides inlength, more often at least about 450 nucleotides in length, more oftenat least about 600 nucleotides in length, more often at least about 900nucleotides in length, or more.

“Percent (%) nucleic acid sequence identity” with respect toPRO-encoding nucleic acid sequences identified herein is defined as thepercentage of nucleotides in a candidate sequence that are identicalwith the nucleotides in the PRO nucleic acid sequence of interest, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity. Alignment for purposes ofdetermining percent nucleic acid sequence identity can be achieved invarious ways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. For purposes herein, however, % nucleicacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for nucleic acid sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:100 times the fraction W/Zwhere W is the number of nucleotides scored as identical matches by thesequence alignment program ALIGN-2 in that program's alignment of C andD, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C. As examples of % nucleic acid sequence identitycalculations. Tables 4 and 5, demonstrate how to calculate the % nucleicacid sequence identity of the nucleic acid sequence designated“Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”,wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acidsequence of interest, “Comparison DNA” represents the nucleotidesequence of a nucleic acid molecule against which the “PRO-DNA” nucleicacid molecule of interest is being compared, and “N”, “L” and “V” eachrepresent different hypothetical nucleotides.

Unless specifically stated otherwise, all % nucleic acid sequenceidentity values used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, %nucleic acid sequence identity values may also be obtained as describedbelow by using the WU-BLAST-2 computer program (Altschul et al., Methodsin Enzymology 266: 460-480 (1996)). Most of the WU-BLAST-2 searchparameters are set to the default values. Those not set to defaultvalues, i.e., the adjustable parameters, are set with the followingvalues: overlap span=1, overlap fraction=0.125, word threshold (T)=11,and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleicacid sequence identity value is determined by dividing (a) the number ofmatching identical nucleotides between the nucleic acid sequence of thePRO polypeptide-encoding nucleic acid molecule of interest having asequence derived from the native sequence PRO polypeptide-encodingnucleic acid and the comparison nucleic acid molecule of interest (i.e.,the sequence against which the PRO polypeptide-encoding nucleic acidmolecule of interest is being compared which may be a variant PROpolynucleotide) as determined by WU-BLAST-2 by (b) the total number ofnucleotides of the PRO polypeptide-encoding nucleic acid molecule ofinterest. For example, in the statement “an isolated nucleic acidmolecule comprising a nucleic acid sequence A which has or having atleast 80% nucleic acid sequence identity to the nucleic acid sequenceB”, the nucleic acid sequence A is the comparison nucleic acid moleculeof interest and the nucleic acid sequence B is the nucleic acid sequenceof the PRO polypeptide-encoding nucleic acid molecule of interest.

Percent amino acid sequence identity may also be determined using thesequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic AcidsRes. 25: 3389-3402 (1997)). NCBI-BLAST2 uses several search parameters,wherein all of those search parameters are set to default valuesincluding, for example, unmask=yes, strand=all, expected occurrences=10,minimum low complexity length=15/5, multi-pass e-value=0.01, constantfor multi-pass=25, dropoff for final gapped alignment=25 and scoringmatrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for sequence comparisons,the % nucleic acid sequence identity of a given nucleic acid sequence Cto, with, or against a given nucleic acid sequence D (which canalternatively be phrased as a given nucleic acid sequence C that has orcomprises a certain % nucleic acid sequence identity to, with, oragainst a given nucleic acid sequence D) is calculated as follows:100 times the fraction W/Zwhere W is the number of nucleotides scored as identical matches by thesequence alignment program NCBI-BLAST2 in that program's alignment of Cand D, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C.

In other embodiments, PRO variant polynucleotides are nucleic acidmolecules that encode an active PRO polypeptide and which arc capable ofhybridizing, preferably under stringent hybridization and washconditions, to nucleotide sequences encoding a full-length PROpolypeptide as disclosed herein. PRO variant polypeptides may be thosethat are encoded by a PRO variant polynucleotide.

The term “positives”, in the context of sequence comparison performed asdescribed above, includes residues in the sequences compared that arenot identical but have similar properties (e.g. as a result ofconservative substitutions, see Table 6 below). For purposes herein, the% value of positives is determined by dividing (a) the number of aminoacid residues scoring a positive value between the PRO polypeptide aminoacid sequence of interest having a sequence derived from the native PROpolypeptide sequence and the comparison amino acid sequence of interest(i.e., the amino acid sequence against which the PRO polypeptidesequence is being compared) as determined in the BLOSUM62 matrix ofWU-BLAST-2 by (b) the total number of amino acid residues of the PROpolypeptide of interest.

Unless specifically stated otherwise, the % value of positives iscalculated as described in the immediately preceding paragraph. However,in the context of the amino acid sequence identity comparisons performedas described for ALIGN-2 and NCBI-BLAST-2 above, includes amino acidresidues in the sequences compared that are not only identical, but alsothose that have similar properties. Amino acid residues that score apositive value to an amino acid residue of interest arc those that areeither identical to the amino acid residue of interest or are apreferred substitution (as defined in Table 6 below) of the amino acidresidue of interest.

For amino acid sequence comparisons using ALIGN-2 or NCBI-BLAST2, the %value of positives of a given amino acid sequence A to, with, or againsta given amino acid sequence B (which can alternatively be phrased as agiven amino acid sequence A that has or comprises a certain % positivesto, with, or against a given amino acid sequence B) is calculated asfollows:100 times the fraction X/Ywhere X is the number of amino acid residues scoring a positive value asdefined above by the sequence alignment program ALIGN-2 or NCBI-BLAST2in that program's alignment of A and B, and where Y is the total numberof amino acid residues in B. It will be appreciated that where thelength of amino acid sequence A is not equal to the length of amino acidsequence B, the % positives of A to B will not equal the % positives ofB to A.

“Isolated,” when used to describe the various polypeptides disclosedherein, means polypeptide that has been identified and separated and/orrecovered from a component of its natural environment. Contaminantcomponents of its natural environment are materials that would typicallyinterfere with diagnostic or therapeutic uses for the polypeptide, andmay include enzymes, hormones, and other proteinaceous ornon-proteinaceous solutes. In preferred embodiments, the polypeptidewill be purified (1) to a degree sufficient to obtain at least 15residues of N-terminal or internal amino acid sequence by use of aspinning cup sequenator, or (2) to homogeneity by SDS-PAGE undernon-reducing or reducing conditions using Coomassie blue or, preferably,silver stain. Isolated polypeptide includes polypeptide in situ withinrecombinant cells, since at least one component of the PRO polypeptidenatural environment will not be present. Ordinarily, however, isolatedpolypeptide will be prepared by at least one purification step.

An “isolated” PRO polypeptide-encoding nucleic acid or otherpolypeptide-encoding nucleic acid is a nucleic acid molecule that isidentified and separated from at least one contaminant nucleic acidmolecule with which it is ordinarily associated in the natural source ofthe polypeptide-encoding nucleic acid. An isolated polypeptide-encodingnucleic acid molecule is other than in the form or setting in which itis found in nature. Isolated polypeptide-encoding nucleic acid moleculestherefore are distinguished from the specific polypeptide-encodingnucleic acid molecule as it exists in natural cells. However, anisolated polypeptide-encoding nucleic acid molecule includespolypeptide-encoding nucleic acid molecules contained in cells thatordinarily express the polypeptide where, for example, the nucleic acidmolecule is in a chromosomal location different from that of naturalcells.

The term “control sequences” refers to DNA sequences necessary for theexpression of an operably linked coding sequence in a particular hostorganism. The control sequences that are suitable for prokaryotes, forexample, include a promoter, optionally an operator sequence, and aribosome binding site. Eukaryotic cells are known to utilize promoters,polyadenylation signals, and enhancers.

Nucleic acid is “operably linked” when it is placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for apresequence or secretory leader is operably linked to DNA for apolypeptide if it is expressed as a preprotein that participates in thesecretion of the polypeptide; a promoter or enhancer is operably linkedto a coding sequence if it affects the transcription of the sequence; ora ribosome binding site is operably linked to a coding sequence if it ispositioned so as to facilitate translation. Generally, “operably linked”means that the DNA sequences being linked are contiguous, and, in thecase of a secretory leader, contiguous and in reading phase. However,enhancers do not have to be contiguous. Linking is accomplished byligation at convenient restriction sites. If such sites do not exist,the synthetic oligonucleotide adaptors or linkers are used in accordancewith conventional practice.

The term “antibody” is used in the broadest sense and specificallycovers, for example, single anti-PRO monoclonal antibodies (includingagonist, antagonist, and neutralizing antibodies), anti-PRO antibodycompositions with polyepitopic specificity, single chain anti-PROantibodies, and fragments of anti-PRO antibodies (see below). The term“monoclonal antibody” as used herein refers to an antibody obtained froma population of substantially homogeneous antibodies, i.e., theindividual antibodies comprising the population are identical except forpossible naturally-occurring mutations that may be present in minoramounts.

“Stringency” of hybridization reactions is readily determinable by oneof ordinary skill in the art, and generally is an empirical calculationdependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperature. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature which can be used. As a result, it follows that higherrelative temperatures would tend to make the reaction conditions morestringent, while lower temperatures less so. For additional details andexplanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley IntersciencePublishers, (1995).

“Stringent conditions” or “high stringency conditions”, as definedherein, may be identified by those that: (1) employ low ionic strengthand high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example. 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mMsodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt'ssolution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10%dextran sulfate at 42° C. with washes at 42° C. in 0.2×SSC (sodiumchloride/sodium citrate) and 50% formamide at 55° C., followed by ahigh-stringency wash consisting of 0.1×SSC containing EDTA at 55° C.

“Moderately stringent conditions” may be identified as described bySambrook et al., Molecular Cloning: A Laboratory Manual, New York: ColdSpring Harbor Press, 1989, and include the use of washing solution andhybridization conditions (e.g., temperature, ionic strength and % SDS)less stringent that those described above. An example of moderatelystringent conditions is overnight incubation at 37° C. in a solutioncomprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate),50 mM sodium phosphate (pH 7.6), 5× Denhardt's solution, 10% dextransulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed bywashing the filters in 1×SSC at about 37-50° C. The skilled artisan willrecognize how to adjust the temperature, ionic strength, etc. asnecessary to accommodate factors such as probe length and the like.

The term “epitope tagged” when used herein refers to a chimericpolypeptide comprising a PRO polypeptide fused to a “tag polypeptide”.The tag polypeptide has enough residues to provide an epitope againstwhich an antibody can be made, yet is short enough such that it does notinterfere with activity of the polypeptide to which it is fused. The tagpolypeptide preferably also is fairly unique so that the antibody doesnot substantially cross-react with other epitopes. Suitable tagpolypeptides generally have at least six amino acid residues and usuallybetween about 8 and 50 amino acid residues (preferably, between about 10and 20 amino acid residues).

As used herein, the term “immunoadhesin” designates antibody-likemolecules which combine the binding specificity of a heterologousprotein (an “adhesin”) with the effector functions of immunoglobulinconstant domains. Structurally, the immunoadhesins comprise a fusion ofan amino acid sequence with the desired binding specificity which isother than the antigen recognition and binding site of an antibody(i.e., is “heterologous”), and an immunoglobulin constant domainsequence. The adhesin part of an immunoadhesin molecule typically is acontiguous amino acid sequence comprising at least the binding site of areceptor or a ligand. The immunoglobulin constant domain sequence in theimmunoadhesin may be obtained from any immunoglobulin, such as IgG-1,IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE,IgD or IgM.

“Active” or “activity” for the purposes herein refers to form(s) of aPRO polypeptide which retain a biological and/or an immunologicalactivity of native or naturally-occurring PRO, wherein “biological”activity refers to a biological function (either inhibitory orstimulatory) caused by a native or naturally-occurring PRO other thanthe ability to induce the production of an antibody against an antigenicepitope possessed by a native or naturally-occurring PRO and an“immunological” activity refers to the ability to induce the productionof an antibody against an antigenic epitope possessed by a native ornaturally-occurring PRO.

The term “antagonist” is used in the broadest sense, and includes anymolecule that partially or fully blocks, inhibits, or neutralizes abiological activity of a native PRO polypeptide disclosed herein. In asimilar manner, the term “agonist” is used in the broadest sense andincludes any molecule that mimics a biological activity of a native PROpolypeptide disclosed herein. Suitable agonist or antagonist moleculesspecifically include agonist or antagonist antibodies or antibodyfragments, fragments or amino acid sequence variants of native PROpolypeptides, peptides, antisense oligonucleotides, small organicmolecules, etc. Methods for identifying agonists or antagonists of a PROpolypeptide may comprise contacting a PRO polypeptide with a candidateagonist or antagonist molecule and measuring a detectable change in oneor more biological activities normally associated with the PROpolypeptide.

“Treatment” refers to both therapeutic treatment and prophylactic orpreventative measures, wherein the object is to prevent or slow down(lessen) the targeted pathologic condition or disorder. Those in need oftreatment include those already with the disorder as well as those proneto have the disorder or those in whom the disorder is to be prevented.

“Chronic” administration refers to administration of the agent(s) in acontinuous mode as opposed to an acute mode, so as to maintain theinitial therapeutic effect (activity) for an extended period of lime.“Intermittent” administration is treatment that is not consecutivelydone without interruption, but rather is cyclic in nature.

“Mammal” for purposes of treatment refers to any animal classified as amammal, including humans, domestic and farm animals, and zoo, sports, orpet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats,rabbits, etc. Preferably, the mammal is human.

Administration “in combination with” one or more further therapeuticagents includes simultaneous (concurrent) and consecutive administrationin any order.

“Carriers” as used herein include pharmaceutically acceptable carriers,excipients, or stabilizers which are nontoxic to the cell or mammalbeing exposed thereto at the dosages and concentrations employed. Oftenthe physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

“Antibody fragments” comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, andFv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng.8(10): 1057-1062 [1995]); single-chain antibody molecules; andmultispecific antibodies formed from antibody fragments.

Papain digestion of antibodies produces two identical antigen-bindingfragments, called “Fab” fragments, each with a single antigen-bindingsite, and a residual “Fc” fragment, a designation reflecting the abilityto crystallize readily. Pepsin treatment yields an F(ab′)₂ fragment thathas two antigen-combining sites and is still capable of cross-linkingantigen.

“Fv” is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This region consists of a dimerof one heavy- and one light-chain variable domain in tight, non-covalentassociation. It is in this configuration that the three CDRs of eachvariable domain interact to define an antigen-binding site on thesurface of the V_(H)-V_(L) dimer. Collectively, the six CDRs conferantigen-binding specificity to the antibody. However, even a singlevariable domain (or half of an Fv comprising only three CDRs specificfor an antigen) has the ability to recognize and bind antigen, althoughat a lower affinity than the entire binding site.

The Fab fragment also contains the constant domain of the light chainand the first constant domain (CH1) of the heavy chain. Fab fragmentsdiffer from Fab′ fragments by the addition of a few residues at thecarboxy terminus of the heavy chain CH1 domain including one or morecysteines from the antibody hinge region. Fab′-SH is the designationherein for Fab′ in which the cysteine residue(s) of the constant domainsbear a free thiol group. F(ab′)₂ antibody fragments originally wereproduced as pairs of Fab′ fragments which have hinge cysteines betweenthem. Other chemical couplings of antibody fragments are also known.

The “light chains” of antibodies (immunoglobulins) from any vertebratespecies can be assigned to one of two clearly distinct types, calledkappa and lambda, based on the amino acid sequences of their constantdomains.

Depending on the amino acid sequence of the constant domain of theirheavy chains, immunoglobulins can be assigned to different classes.There are five major classes of immunoglobulins: IgA, IgD, TgE, IgG, andIgM, and several of these may be further divided into subclasses(isotypes), e.g., IgG1, IgG2. IgG3, IgG4, IgA, and IgA2.

“Single-chain Fv” or “sFv” antibody fragments comprise the V_(H) andV_(L) domains of antibody, wherein these domains are present in a singlepolypeptide chain. Preferably, the Fv polypeptide further comprises apolypeptide linker between the V_(H) and V_(L) domains which enables thesFv to form the desired structure for antigen binding. For a review ofsFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315(1994).

The term “diabodies” refers to small antibody fragments with twoantigen-binding sites, which fragments comprise a heavy-chain variabledomain (V_(H)) connected to a light-chain variable domain (V_(L)) in thesame polypeptide chain (V_(H)-V_(L)). By using a linker that is tooshort to allow pairing between the two domains on the same chain, thedomains are forced to pair with the complementary domains of anotherchain and create two antigen-binding sites. Diabodies arc described morefully in, for example, EP 404,097; WO 93/11161; and Hollinger et al.,Proc. Natl. Acad. Sci. USA, 90: 6444-6448 (1993).

An “isolated” antibody is one which has been identified and separatedand/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials whichwould interfere with diagnostic or therapeutic uses for the antibody,and may include enzymes, hormones, and other proteinaceous ornonproteinaceous solutes. In preferred embodiments, the antibody will bepurified (1) to greater than 95% by weight of antibody as determined bythe Lowry method, and most preferably more than 99% by weight, (2) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step.

The word “label” when used herein refers to a detectable compound orcomposition which is conjugated directly or indirectly to the antibodyso as to generate a “labeled” antibody. The label may be detectable byitself (e.g. radioisotope labels or fluorescent labels) or, in the caseof an enzymatic label, may catalyze chemical alteration of a substratecompound or composition which is detectable.

By “solid phase” is meant a non-aqueous matrix to which the antibody ofthe present invention can adhere. Examples of solid phases encompassedherein include those formed partially or entirely of glass (e.g.,controlled pore glass), polysaccharides (e.g., agarose),polyacrylamides, polystyrene, polyvinyl alcohol and silicones. Incertain embodiments, depending on the context, the solid phase cancomprise the well of an assay plate; in others it is a purificationcolumn (e.g., an affinity chromatography column). This term alsoincludes a discontinuous solid phase of discrete particles, such asthose described in U.S. Pat. No. 4,275,149.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as a PRO polypeptide or antibody thereto) to a mammal. Thecomponents of the liposome are commonly arranged in a bilayer formation,similar to the lipid arrangement of biological membranes.

A “small molecule” is defined herein to have a molecular weight belowabout 500 Daltons.

TABLE 1 /*  *  * C—C increased from 12 to 15  * Z is average of EQ  * Bis average of ND  * match with stop is _M; stop—stop = 0; J (joker)match = 0  */ #define _M −8 /* value of a match with a stop */ int_day[26][26] = { /* A B C D E F G H I J K L M N O P Q R S T U V W X Y Z*/ /* A */ {2, 0,−2, 0, 0,−4, 1,−1,−1, 0,−1,−2,−1, 0,_M, 1, 0,−2, 1, 1,0, 0,−6, 0,−3, 0}, /* B */ { 0, 3,−4, 3, 2,−5, 0, 1,−2, 0, 0,−3,−2,2,_M,−1, 1, 0, 0, 0, 0,−2,−5, 0,−3, 1}, /* C */ {−2,−4,15,−5,−5,−4,−3,−3,−2, 0,−5,−6,−5,−4,_M,−3,−5,−4, 0,−2, 0,−2,−8, 0,0,−5}, /* D */ { 0, 3,−5, 4, 3,−6, 1, 1,−2, 0, 0,−4,−3, 2,_M,−1, 2,−1,0, 0, 0,−2,−7, 0,−4, 2}, /* E */ { 0, 2,−5, 3, 4,−5, 0, 1,−2, 0,0,−3,−2, 1,_M,−1, 2,−1, 0, 0, 0,−2,−7, 0,−4, 3}, /* F */{−4,−5,−4,−6,−5, 9,−5,−2, 1, 0,−5, 2, 0,−4,_M,−5,−5,−4,−3,−3, 0,−1, 0,0, 7,−5}, /* G */ { 1, 0,−3, 1, 0,−5, 5,−2,−3, 0,−2,−4,−3,0,_M,−1,−1,−3, 1, 0, 0,−1,−7, 0,−5, 0}, /* H */ {−1, 1,−3, 1, 1,−2,−2,6,−2, 0, 0,−2,−2, 2,_M, 0, 3, 2,−1,−1, 0,−2,−3, 0, 0, 2}, /* I */{−1,−2,−2,−2,−2, 1,−3,−2, 5, 0,−2, 2, 2,−2,_M,−2,−2,−2,−1, 0, 0, 4,−5,0,−1,−2}, /* J */ { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0,0, 0, 0, 0, 0, 0, 0, 0, 0}, /* K */ {−1, 0,−5, 0, 0,−5,−2, 0,−2, 0,5,−3, 0, 1,_M,−1, 1, 3, 0, 0, 0,−2,−3, 0,−4, 0}, /* L */{−2,−3,−6,−4,−3, 2,−4,−2, 2, 0,−3, 6, 4,−3,_M,−3,−2,−3,−3,−1, 0, 2,−2,0,−1,−2}, /* M */ {−1,−2,−5,−3,−2, 0,−3,−2, 2, 0, 0, 4, 6,−2,_M,−2,−1,0,−2,−1, 0, 2,−4, 0,−2,−1}, /* N */ { 0, 2,−4, 2, 1,−4, 0, 2,−2, 0,1,−3,−2, 2,_M,−1, 1, 0, 1, 0, 0,−2,−4, 0,−2, 1}, /* O */{_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,0,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M}, /* P */ { 1,−1,−3,−1,−1,−5,−1,0,−2, 0,−1,−3,−2,−1,_M, 6, 0, 0, 1, 0, 0,−1,−6, 0,−5, 0}, /* Q */ { 0,1,−5, 2, 2,−5,−1, 3,−2, 0, 1,−2,−1, 1,_M, 0, 4, 1,−1,−1, 0,−2,−5, 0,−4,3}, /* R */ {−2, 0,−4,−1,−1,−4,−3, 2,−2, 0, 3,−3, 0, 0,_M, 0, 1, 6,0,−1, 0,−2, 2, 0,−4, 0}, /* S */ { 1, 0, 0, 0, 0,−3, 1,−1,−1, 0,0,−3,−2, 1,_M, 1,−1, 0, 2, 1, 0,−1,−2, 0,−3, 0}, /* T */ { 1, 0,−2, 0,0,−3, 0,−1, 0, 0, 0,−1,−1, 0,_M, 0,−1,−1, 1, 3, 0, 0,−5, 0,−3, 0}, /* U*/ { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0,0, 0, 0, 0}, /* V */ { 0,−2,−2,−2,−2,−1,−1,−2, 4, 0,−2, 2,2,−2,_M,−1,−2,−2,−1, 0, 0, 4,−6, 0,−2,−2}, /* W */ {−6,−5,−8,−7,−7,0,−7,−3,−5, 0,−3,−2,−4,−4,_M,−6,−5, 2,−2,−5, 0,−6, 17, 0, 0,−6}, /* X */{ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0,0, 0, 0}, /* Y */ {−3,−3, 0,−4,−4, 7,−5, 0,−1,0,−4,−1,−2,−2,_M,−5,−4,−4,−3,−3, 0,−2, 0, 0, 10,−4}, /* Z */ { 0, 1,−5,2, 3,−5, 0, 2,−2, 0, 0,−2,−1, 1,_M, 0, 3, 0, 0, 0, 0,−2,−6, 0,−4, 4} };/*  */ #include < stdio.h > #include < ctype.h > #define MAXJMP 16 /*max jumps in a diag */ #define MAXGAP 24 /* don't continue to penalizegaps larger than this */ #define JMPS 1024 /* max jmps in an path */#define MX 4 /* save if there's at least MX−1 bases since last jmp */#define DMAT 3 /* value of matching bases */ #define DMIS 0 /* penaltyfor mismatched bases */ #define DINS0 8 /* penalty for a gap */ #defineDINS1 1 /* penalty per base */ #define PINS0 8 /* penalty for a gap */#define PINS1 4 /* penalty per residue */ struct jmp { short n[MAXJMP];/* size of jmp (neg for dely) */ unsigned short x[MAXJMP]; /* base no.of jmp in seq x */ }; /* limits seq to 2{circumflex over ( )}16 −1 */struct diag { int score; /* score at last jmp */ long offset; /* offsetof prev block */ short ijmp; /* current jmp index */ struct jmp jp; /*list of jmps */ }; struct path { int spc; /* number of leading spaces */short n[JMPS];/* size of jmp (gap) */ int x[JMPS];/* loc of jmp (lastelem before gap) */ }; char *ofile; /* output file name */ char*namex[2]; /* seq names: getseqs( ) */ char *prog; /* prog name for errmsgs */ char *seqx[2]; /* seqs: getseqs( ) */ int dmax; /* best diag:nw( ) */ int dmax0; /* final diag */ int dna; /* set if dna: main( ) */int endgaps; /* set if penalizing end gaps */ int gapx, gapy; /* totalgaps in seqs */ int len0, len1; /* seq lens */ int ngapx, ngapy; /*total size of gaps */ int smax; /* max score: nw( ) */ int *xbm; /*bitmap for matching */ long offset; /* current offset in jmp file */struct diag *dx; /* holds diagonals */ struct path pp[2]; /* holds pathfor seqs */ char *calloc( ), *malloc( ), *index( ), *strcpy( ); char*getseq( ), *g_calloc( ); /* Needleman-Wunsch alignment program  *  *usage: progs file1 file2  * where file1 and file2 are two dna or twoprotein sequences.  * The sequences can be in upper- or lower-case anmay contain ambiguity  * Any lines beginning with ‘;’, ‘>’ or ‘<’ areignored  * Max file length is 65535 (limited by unsigned short x in thejmp struct)  * A sequence with ⅓ or more of its elements ACGTU isassumed to be DNA  * Output is in the file “align.out”  *  * The programmay create a tmp file in /tmp to hold info about traceback.  * Originalversion developed under BSD 4.3 on a vax 8650  */ #include “nw.h”#include “day.h” static _dbval[26] = {1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0 }; static_pbval[26] = { 1, 2|(1< <(‘D’−‘A’))|(1< <(‘N’−‘A’)), 4, 8, 16, 32, 64,128, 256, 0xFFFFFFF, 1< <10, 1< <11, 1< <12, 1< <13, 1< <14, 1< <15, 1<<16, 1< <17, 1< <18, 1< <19, 1< <20, 1< <21, 1< <22, 1< <23, 1< <24, 1<<25|(1< <(‘E’−‘A’))|(1< <(‘Q’−‘A’)) }; main(ac, av) main int ac; char*av[ ]; { prog = av[0]; if (ac != 3) { fprintf(stderr,“usage: %s file1file2\n”, prog); fprintf(stderr,“where file1 and file2 are two dna ortwo protein sequences.\n”); fprintf(stderr,“The sequences can be inupper- or lower-case\n”); fprintf(stderr,“Any lines beginning with ‘;’or ‘<’ are ignored\n”); fprintf(stderr,“Output is in the file\”align.out\ “\n”); exit(1); } namex[0] = av[1]; namex[1] = av[2];seqx[0] = getseq(namex[0], &len0); seqx[1] = getseq(namex[1], &len1);xbm = (dna)? _dbval : _pbval; endgaps = 0; /* 1 to penalize endgaps */ofile = “align.out”; /* output file */ nw( ); /* fill in the matrix, getthe possible jmps */ readjmps( ); /* get the actual jmps */ print( ); /*print stats, alignment */ cleanup(0); /* unlink any tmp files */ } /* dothe alignment, return best score: main( )  * dna: values in Fitch andSmith, PNAS, 80, 1382-1386, 1983  * pro: PAM 250 values  * When scoresare equal, we prefer mismatches to any gap, prefer  * a new gap toextending an ongoing gap, and prefer a gap in seqx  * to a gap in seq y. */ nw( ) nw { char *px, *py; /* seqs and ptrs */ int *ndely, *dely; /*keep track of dely */ int ndelx, delx; /* keep track of delx */ int*tmp; /* for swapping row0, row1 */ int mis; /* score for each type */int ins0, ins1; /* insertion penalties */ register id; /* diagonal index*/ register ij; /* jmp index */ register *col0, *col1; /* score forcurr, last row */ register xx, yy; /* index into seqs */ dx = (structdiag *)g_calloc(*to get diags*, len0 + len1 + 1, sizeof(struct diag));ndely = (int *)g_calloc(“to get ndely”, len1 + 1, sizeof(int)); dely =(int *)g_calloc(“to get dely”, len1 + 1, sizeof(int)); col0 = (int*)g_calloc(“to get col0”, len1 + 1, sizeof(int)); col1 = (int*)g_calloc(“to get col1”, len1 + 1, sizeof(int)); ins0 = (dna)? DINS0 :PINS0; ins1 = (dna)? DINS1 : PINS1; smax = −10000; if (endgaps) { for(col0[0] = dely[0] = −ins0, yy = 1; yy < = len1; yy + +) { col0[yy] =dely[yy] = col0[yy−1] − ins1; ndely[yy] = yy; } col0[0] = 0;   /*Waterman Bull Math Biol 84 */ } else for (yy = 1; yy < = len1; yy + +)dely[yy] = −ins0; /* fill in match matrix  */ for (px = seqx[0], xx = 1;xx < = len0; px + +, xx + +) { /* initialize first entry in col  */ if(endgaps) { if (xx = = 1) col1[0] = delx = −(ins0 + ins1); else col1[0]= delx = col0[0] − ins1; ndelx = xx; } else { col1[0] = 0; delx = −ins0;ndelx = 0; } for (py = seqx[1], yy = 1; yy < = len1; py + +, yy + +) {mis = col0[yy−1]; if (dna) mis + = (xbm[*px−‘A’]&xbm[*py−‘A’])? DMAT :DMIS; else mis + = _day[*px−‘A’][*py−‘A’]; /* update penalty for del inx seq;  * favor new del over ongong del  * ignore MAXGAP if weightingendgaps  */ if (endgaps | | ndely[yy] < MAXGAP) { if (col0[yy] − ins0 >= dely[yy]) { dely[yy] = col0[yy] − (ins0 + ins1); ndely[yy] = 1; } else{ dely[yy] −= ins1; ndely[yy] + +; } } else { if (col0[yy] − (ins0 +ins1) > = dely[yy]) { dely[yy] = col0[yy] − (ins0 + ins1); ndely[yy] =1; } else ndely[yy] + +; } /* update penalty for del in y seq;  * favornew del over ongong del  */ if (endgaps | | ndelx < MAXGAP) { if(col1[yy−1] − ins0 > = delx) { delx = col1[yy−1] − (ins0 + ins1); ndelx= 1; } else { delx − = ins1; ndelx + +; } } else { if (col1[yy−1] −(ins0 + ins1) > = delx) { delx = col1[yy−1] − (ins0 + ins1); ndelx = 1;} else ndelx + +; } /* pick the maximum score; we're favoring  * misover any del and delx over dely  */ id = xx − yy + len1 − 1; if (mis > =delx && mis > = dely[yy]) col1[yy] = mis; else if (delx > = dely[yy]) {col1[yy] = delx; ij = dx[id].ijmp; if (dx[id].jp.n[0] && (!dna | |(ndelx > = MAXJMP && xx > dx[id].jp.x[ij] + MX) | | mis > dx[id].score +DINS0)) { dx[id].ijmp + +; if ( + + ij > = MAXJMP) { writejmps(id); ij =dx[id].ijmp = 0; dx[id].offset = offset; offset + = sizeof(struct jmp) +sizeof(offset); } } dx[id].jp.n[ij] = ndelx; dx[id].jp.x[ij] = xx;dx[id].score = delx; } else { col1[yy] = dely[yy]; ij = dx[id].ijmp; if(dx[id].jp.n[0] && (!dna | | (ndely[yy] > = MAXJMP && xx >dx[id].jp.x[ij] + MX) | | mis > dx[id].score + DINS0)) { dx[id].ijmp ++; if ( + + ij > = MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0;dx[id].offset = offset; offset + = sizeof(struct jmp) + sizeof(offset);} } dx[id].jp.n[ij] = −ndely[yy]; dx[id].jp.x[ij] = xx; dx[id].score =dely[yy]; } if (xx = = len0 && yy < len1) { /* last col  */ if (endgaps)col1[yy] − = ins0 + ins1*(len1−yy); if (col1[yy] > smax) { smax =col1[yy]; dmax = id; } } } if (endgaps && xx < len0) col1[yy−1] −=ins0 + ins1*(len0−xx); if (col1[yy−1] > smax) { smax = col1[yy−1]; dmax= id; } tmp = col0; col0 = col1; col1 = tmp; } (void) free((char*)ndely); (void) free((char *)dely); (void) free((char *)col0); (void)free((char *)col1); } /*  *  * print( ) -- only routine visible outsidethis module  *  * static:  * getmat( ) -- trace back best path, countmatches: print( )  * pr_align( ) -- print alignment of described inarray p[ ]: print( )  * dumpblock( ) -- dump a block of lines withnumbers, stars: pr_align( )  * nums( ) -- put out a number line:dumpblock( )  * putline( ) -- put out a line (name, [num], seq, [num]):dumpblock( )  * stars( ) -- put a line of stars: dumpblock( )  *stripname( ) -- strip any path and prefix from a seqname  */ #include“nw.h” #define SPC 3 #define P_LINE 256 /* maximum output line */#define P_SPC 3 /* space between name or num and seq */ extern_day[26][26]; int olen; /* set output line length */ FILE *fx; /* outputfile */ print( ) print { int lx, ly, firstgap, lastgap; /* overlap */ if((fx = fopen(ofile, “w”)) = = 0) { fprintf(stderr,“%s: can't write&s\n”, prog, ofile); cleanup(1); } fprintf(fx, “< first sequence: %s(length = %d)\n”, namex[0], len0); fprintf(fx, “< second sequence: %s(length = %d)\n”, namex[1], len1); olen = 60; lx = len0; ly = len1;firstgap = lastgap = 0; if (dmax < len1 − 1) {  /* leading gap in x */pp[0].spc = firstgap = len1 − dmax − 1; ly −= pp[0].spc; } else if(dmax > len1 − 1) { /* leading gap in y */ pp[1].spc = firstgap = dmax −(len1 − 1); lx −= pp[1].spc; } if (dmax0 < len0 − 1) {  /* trailing gapin x */ lastgap = len0 − dmax0 −1; lx −= lastgap; } else if (dmax0 >len0 − 1) { /* trailing gap in y */ lastgap = dmax0 − (len0 − 1); ly −=lastgap; } getmat(lx, ly, firstgap, lastgap); pr_align( ); } /*  * traceback the best path, count matches  */ static getmat(lx, ly, firstgap,lastgap) getmat int lx, ly; /* “core” (minus endgaps) */ int firstgap,lastgap; /* leading trailing overlap */ { int nm, i0, i1, siz0, siz1;char outx[32]; double pct; register n0, n1; register char *p0, *p1; /*get total matches, score  */ i0 = i1 = siz0 = siz1 = 0; p0 = seqx[0] +pp[1].spc; p1 = seqx[1] + pp[0].spc; n0 = pp[1].spc + 1; n1 =pp[0].spc + 1; nm = 0; while ( *p0 && *p1 ) { if (siz0) { p1 + +; n1 ++; siz0−−; } else if (siz1) { p0 + +; n0 + +; siz1−−; } else { if(xbm[*p0−‘A’]&xbm[*p1−‘A’]) nm + +; if (n0 + + = = pp[0].x[i0]) siz0 =pp[0].n[i0 + +]; if (n1 + + = = pp[1].x[i1]) siz1 = pp[1].n[i1 + +];p0 + +; p1 + +; } } /* pct homology:  * if penalizing endgaps, base isthe shorter seq  * else, knock off overhangs and take shorter core  */if (endgaps) lx = (len0 < len1)? len0 : len1; else lx = (lx < ly)? lx :ly; pct = 100.*(double)nm/(double)lx; fprintf(fx, “\n”); fprintf(fx, “<%d match %s in an overlap of %d: %.2f percent similarity\n”, nm, (nm = =1)? “ ” : “es”, lx, pct); fprintf(fx, “< gaps in first sequence: %d”,gapx); if (gapx) { (void) sprintf(outx, “ (%d %s%s)”, ngapx, (dna)?“base”:“residue”, (ngapx = = 1)? “ ”:“s”); fprintf(fx, “%s”, outx);fprintf(fx, “, gaps in second sequence: %d”, gapy); if (gapy) { (void)sprintf(outx, “ (%d %s%s)”, ngapy, (dna)? “base”:“residue”, (ngapy = =1)? “ ”:“s”); fprintf(fx, “%s”, outx); } if (dna) fprintf(fx, “\n<score:%d (match = %d, mismatch = %d, gap penalty = %d + %d per base)\n”, smax,DMAT, DMIS, DINS0, DINS1); else fprintf(fx, “\n<score: %d (Dayhoff PAM250 matrix, gap penalty = %d + %d per residue)\n”, smax, PINS0, PINS1);if (endgaps) fprintf(fx, “< endgaps penalized, left endgap; %d %s%s,right endgap: %d %s%s\n”, firstgap, (dna)? “base” : “residue”, (firstgap= = 1)? “ ” : “s”, lastgap, (dna)? “base” : “residue”, (lastgap = = 1)?“ ” : “s”); else fprintf(fx, “< endgaps not penalized\n”); } static nm;/* matches in core -- for checking */ static lmax; /* lengths ofstripped file names */ static ij[2]; /* jmp index for a path */ staticnc[2]; /* number at start of current line */ static ni[2]; /* currentelem number -- for gapping */ static siz[2]; static char *ps[2]; /* ptrto current element */ static char *po[2]; /* ptr to next output charslot */ static char out[2][P_LINE]; /* output line */ static charstar[P_LINE]; /* set by stars( ) */ /*  * print alignment of describedin struct path pp[ ]  */ static pr_align( ) pr_align { int nn; /* charcount */ int more; register i; for (i = 0, lmax = 0; i < 2; i + +) { nn= stripname(namex[i]); if (nn > lmax) lmax = nn; nc[i] = 1; ni[i] = 1;siz[i] = ij[i] = 0; ps[i] = seqx[i]; po[i] = out[i]; } for (nn = nm = 0,more = 1; more; ) { for (i = more = 0; i < 2; i + +) { /*  * do we havemore of this sequence?  */ if (!*ps[i]) continue; more+ +; if(pp[i].spc) {  /* leading space */ *po[i] + + = ‘ ’; pp[i].spc−−; } elseif (siz[i]) {  /* in a gap */ *po[i] + + = ‘−’; siz[i]−−; } else { /*we're putting a seq element  */ *po[i] = *ps[i]; if (islower(*ps[i]))*ps[i] = toupper(*ps[i]); po[i] + +; ps[i] + +; /*  * are we at next gapfor this seq?  */ if (ni[i] = = pp[i].x[ij[i]]) { /*  * we need to mergeall gaps  * at this location  */ siz[i] = pp[i].n[ij[i] + +]; while(ni[i] = = pp[i].x[ij[i]]) siz[i] + = pp[i].n[ij[i] + +]; } ni[i] + +; }} if ( + + nn = = olen | | !more && nn) { dumpblock( ); for (i = 0; i <2; i + +) po[i] = out[i]; nn = 0; } } } /*  * dump a block of lines,including numbers, stars: pr_align( )  */ static dumpblock( ) dumpblock{ register i; for (i = 0; i < 2; i + +) *po[i] −− = ‘\0’; (void)putc(‘\n’, fx); for (i = 0; i < 2; i + +) { if (*out[i] && (*out[i] != ‘’ | | *(po[i]) != ‘ ’)) { if (i = = 0) nums(i); if (i = = 0 && *out[1])stars( ); putlinc(i); if (i = = 0 && *out[1]) fprintf(fx, star); if (i == 1) nums(i); } } } /*  * put out a number line: dumpblock( )  */ staticnums(ix) nums int ix; /* index in out[ ] holding seq line */ { charnline[P_LINE]; register i, j; register char *pn, *px, *py; for (pn =nline, i = 0; i < lmax + P_SPC; i + +, pn + +) *pn = ‘ ’; for (i =nc[ix], py = out[ix]; *py; py + +, pn + +) { if (*py = = ‘ ’ | | *py = =‘−’) *pn = ‘ ’; else { if (i% 10 = = 0 | | (i = = 1 && nc[ix] != 1)) { j= (i < 0)? −i : i; for (px = pn; j; j /= 10, px−−) *px = j%10 + ‘0’; if(i < 0) *px = ‘−’; } else *pn = ‘ ’; i + +; } } *pn = ‘\0’; nc[ix] = i;for (pn = nline; *pn; pn + +) (void) putc(*pn, fx); (void) putc(‘\n’,fx); } /*  * put out a line (name, [num], seq, [num]): dumpblock( )  */static putline(ix) putline int ix; { int i; register char *px; for (px =namex[ix], i = 0; *px && *px != ‘:’; px + +, i + +) (void) putc(*px,fx); for (; i < lmax+P_SPC; i + +) (void) putc(‘ ’, fx); /* these countfrom 1:  * ni[ ] is current element (from 1)  * nc[ ] is number at startof current line  */ for (px = out[ix]; *px; px + +) (void)putc(*px&0x7F, fx); (void) putc(‘\n’, fx); } /*  * put a line of stars(seqs always in out[0], out[1]): dumpblock( )  */ static stars( ) stars{ int i; register char *p0, *p1, cx, *px; if (!*out[0] | | (*out[0] = =‘ ’ && *(po[0]) = = ‘ ’) | |   !*out[1] | | (*out[1] = = ‘ ’ && *(po[1])= = ‘ ’)) return; px = star; for (i = lmax + P_SPC; i; i−−) *px + + = ‘’; for (p0 = out[0], p1 = out[1]; *p0 && *p1; p0 + +, p1 + +) { if(isalpha(*p0) && isalpha(*p1)) { if (xbm[*p0−‘A’]&xbm[*p1−‘A’]) { cx =‘*’; nm + +; } else if (!dna && _day[*p0−‘A’][*p1−‘A’] > 0) cx = ‘.’;else cx = ‘ ’; } else cx = ‘ ’; *px + + = cx; } *px + + = ‘\n’; *px =‘\0’; } /*  * strip path or prefix from pn, return len: pr_align( )  */static stripname(pn) stripname char *pn; /* file name (may be path) */ {register char *px, *py; py = 0; for (px = pn; *px; px + +) if (*px = =‘/’) py = px + 1; if (py) (void) strcpy(pn, py); return(strlen(pn)); }/*  * cleanup( ) -- cleanup any tmp file  * getseq( ) -- read in seq,set dna, len, maxlen  * g_calloc( ) -- calloc( ) with error checkin  *readjmps( ) -- get the good jmps, from tmp file if necessary  *writejmps( ) -- write a filled array of jmps to a tmp file: nw( )  */#include “nw.h” #include <sys/file.h> char *jname = “/tmp/homgXXXXXX”;/* tmp file for jmps */ FILE *fj; int cleanup( ); /* cleanup tmp file */long lseek( ); /*  * remove any tmp file if we blow  */ cleanup(i)cleanup int i; { if (fj) (void) unlink(jname); exit(i); } /*  * read,return ptr to seq, set dna, len, maxlen  * skip lines starting with ‘;’,‘<’, or ‘>’  * seq in upper or lower case  */ char * getseq(file, len)getseq char *file; /* file name */ int *len; /* seq len */ { charline[1024], *pseq; register char *px, *py; int natgc, tlen; FILE *fp; if((fp = fopen(file, “r”)) = = 0) { fprintf(stderr,“%s: can't read %s\n”,prog, file); exit(1); } tlen = natgc = 0; while (fgets(line, 1024, fp)){ if (*line = = ‘:’ | | *line = = ‘<’ | | *line = = ‘>’) continue; for(px = line; *px != ‘\n’; px + +) if (isupper(*px) | | islower(*px))tlen + +; } if ((pseq = malloc((unsigned)(tlen + 6))) = = 0) {fprintf(stderr, “%s: malloc( ) failed to get %d bytes for %s\n”, prog,tlen + 6, file); exit(1); } pseq[0] = pseq[1] = pseq[2] = pseq[3] =‘\0’; py = pseq + 4; *len = tlen; rewind(fp); while (fgets(line, 1024,fp)) { if (*line = = ‘;’ | | *line = = ‘<’ | | *line = = ‘>’) continue;for (px = line; *px != ‘\n’; px + +) { if (isupper(*px)) *py + + = *px;else if (islower(*px)) *py + + = toupper(*px); if(index(“ATGCU”,*(py−1))) natgc + +; } } *py + + = ‘\0’; *py = ‘\0’;(void) fclose(fp); dna = natgc > (tlen/3); return(pseq + 4); } char *g_calloc(msg, nx, sz) g_calloc char *msg; /* program, calling routine */int nx, sz; /* number and size of elements */ { char *px, *calloc( ); if((px = calloc((unsigned)nx, (unsigned)sz)) = = 0) { if (*msg) {fprintf(stderr, “%s: g_calloc( ) failed %s (n = %d, sz = %d)\n”, prog,msg, nx, sz); exit(1); } } return(px); } /*  * get final jmps from dx[ ]or tmp file, set pp[ ], reset dmax: main( )  */ readjmps( ) { readjmpsint fd = −1; int siz, i0, i1; register i, j, xx; if (fj) { (void)fclose(fj); if ((fd = open(jname, O_RDONLY, 0)) < 0) { fprintf(stderr,“%s: can't open( ) %s\n”, prog, jname); cleanup(1); } } for (i = i0 = i1= 0, dmax0 = dmax, xx = len0; ; i + +) { while (1) { for (j =dx[dmax].ijmp; j > = 0 && dx[dmax].jp.x[j] > = xx; j−−); if (j < 0 &&dx[dmax].offset && fj) { (void) lseek(fd, dx[dmax].offset, 0); (void)read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp)); (void) read(fd,(char *)&dx[dmax].offset, sizeof(dx[dmax].offset)); dx[dmax].ijmp =MAXJMP−1; } else break; } if (i > = JMPS) { fprintf(stderr, “%s: toomany gaps in alignment\n”, prog); cleanup(1); } if (j > = 0) { siz =dx[dmax].jp.n[j]; xx = dx[dmax].jp.x[j]; dmax + = siz; if (siz < 0) { /*gap in second seq */ pp[1].n[i1] = −siz; xx + = siz; /* id = xx − yy +len1 − 1  */ pp[1].x[i1] = xx − dmax + len1 − 1; gapy + +; ngapy −= siz;/* ignore MAXGAP when doing endgaps */ siz = (−siz < MAXGAP | |endgaps)? −siz : MAXGAP; i1 + +; } else if (siz > 0) { /* gap in firstseq */ pp[0].n[i0] = siz; pp[0].x[i0] = xx; gapx + +; ngapx + = siz; /*ignore MAXGAP when doing endgaps */ siz = (siz < MAXGAP | | endgaps)?siz : MAXGAP; i0 + +; } } else break; } /* reverse the order of jmps  */for (j = 0, i0−−; j < i0; j + +, i0−−) { i = pp[0].n[j]; pp[0].n[j] =pp[0].n[i0]; pp[0].n[i0] = i; i = pp[0].x[j]; pp[0].x[j] = pp[0].x[i0];pp[0].x[i0] = i; } for (j = 0, i1−−; j < i1; j + +, i1−−) { i =pp[1].n[j]; pp[1].n[j] = pp[1].n[i1]; pp[1].n[i1] = i; i = pp[1].x[j];pp[1].x[j] = pp[1].x[i1]; pp[1].x[i1] = i; } if (fd > = 0) (void)close(fd); if (fj) { (void) unlink(jname); fj = 0; offset = 0; } } /*  *write a filled jmp struct offset of the prev one (if any): nw( )  */writejmps(ix) writejmps int ix; { char *mktemp( ); if (!fj) { if(mktemp(jname) < 0) { tprintf(stderr, “%s: can't mktemp( ) %s\n”, prog,jname); cleanup(1); } if ((fj = fopen(jname, “w”)) = = 0) {fprintf(stderr, “%s: can't write %s\n”, prog, jname); exit(1); } }(void) fwrite((char *)&dx[ix].jp, sizeof(struct jmp), 1, fj); (void)fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj); }

TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) ComparisonXXXXXYYYYYYY (Length = 12 amino acids) Protein % amino acid sequenceidentity = (the number of identically matching amino acid residuesbetween the two polypeptide sequences as determined by ALIGN-2) dividedby (the total number of amino acid residues of the PRO polypeptide) = 5divided by 15 = 33.3%

TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids) ComparisonXXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein % amino acid sequenceidentity = (the number of identically matching amino acid residuesbetween the two polypeptide sequences as determined by ALIGN-2) dividedby (the total number of amino acid residues of the PRO polypeptide) = 5divided by 10 = 50%

TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides) ComparisonNNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA % nucleic acid sequenceidentity = (the number of identically matching nucleotides between thetwo nucleic acid sequences as determined by ALIGN-2) divided by (thetotal number of nucleotides of the PRO-DNA nucleic acid sequence) = 6divided by 14 = 42.9%

TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) Comparison DNANNNNLLLVV (Length = 9 nucleotides) % nucleic acid sequence identity =(the number of identically matching nucleotides between the two nucleicacid sequences as determined by ALIGN-2) divided by (the total number ofnucleotides of the PRO-DNA nucleic acid sequence) = 4 divided by 12 =33.3%II. Compositions and Methods of the Invention

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO polypeptides. In particular, cDNAs encoding various PROpolypeptides have been identified and isolated, as disclosed in furtherdetail in the Examples below. It is noted that proteins produced inseparate expression rounds may be given different PRO numbers but theUNQ number is unique for any given DNA and the encoded protein, and willnot be changed. However, for sake of simplicity, in the presentspecification the protein encoded by the full length native nucleic acidmolecules disclosed herein as well as all further native homologues andvariants included in the foregoing definition of PRO, will be referredto as “PRO/number”, regardless of their origin or mode of preparation.

As disclosed in the Examples below, various cDNA clones have beendeposited with the ATCC. The actual nucleotide sequences of those clonescan readily be determined by the skilled artisan by sequencing of thedeposited clone using routine methods in the art. The predicted aminoacid sequence can be determined from the nucleotide sequence usingroutine skill. For the PRO polypeptides and encoding nucleic acidsdescribed herein, Applicants have identified what is believed to be thereading frame best identifiable with the sequence information availableat the time.

A. Full-Length PRO Polypeptides

1. PRO1560

Using the WU-BLAST2 sequence alignment computer program, the full-lengthnative sequence PRO1560 (shown in FIG. 2 and SEQ ID NO:4) has certainamino acid sequence identity with Tspan-6, identified after thediscovery of the present invention herein. Accordingly, it is presentlybelieved that PRO1560 disclosed in the present application is a newlyidentified member of the tetraspan family.

2. PRO444

The DNA26846-1397 clone was isolated from a human fetal lung libraryusing a trapping technique which selects for nucleotide sequencesencoding secreted proteins. Thus, the DNA26846-1397 clone encodes asecreted factor. As far as is known, the DNA26846-1397 sequence encodesa novel factor designated herein as PRO444. Using the WU-BLAST2 sequencealignment computer program, no significant sequence identity with knownproteins was revealed.

3. PRO1018

The DNA56107-1415 clone was isolated from a human ovary tumor tissuelibrary using a trapping technique which selects for nucleotidesequences encoding secreted proteins. As far as is known, theDNA56107-1415 sequence encodes a novel factor designated herein asPRO1018; using the WU-BLAST2 sequence alignment computer program, nosignificant sequence identities to any known proteins were revealed.

4. PRO1773

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1773 (shownin FIG. 8 and SEQ ID NO:10) has certain amino acid sequence identitywith a portion of the retinol dehydrogenase type 11 protein of rattusnorvegicus (ROH2_RAT). Accordingly, it is presently believed thatPRO1773 disclosed in the present application is a newly identifiedmember of the retinol dehydrogenase protein family and may possessactivity typical of that protein family.

5. PRO1477

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1477 (shown in FIG. 10 andSEQ ID NO:12) has certain amino acid sequence identity with themannosyl-oligosaccharide 1,2-alpha-mannosidase protein (A54408).Accordingly, it is presently believed that PRO1477 disclosed in thepresent application is a newly identified member of the mannosidaseprotein family and may possess activity typical of the mannosidaseprotein family.

6. PRO1478

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1478 (shown in FIG. 12 and SEQ IDNO:17) has certain amino acid sequence identity withgalactosyltransferases. Accordingly, it is presently believed thatPRO1478 disclosed in the present application is a newly identifiedmember of the galactosyltransferase family and may possess at least oneshared mechanism with other members of this family.

7. PRO831

The DNA56862-1343 clone was isolated from a human uterus library using atrapping technique which selects for nucleotide sequences encodingsecreted proteins. Thus, the DNA56862-1343 clone does encode a secretedfactor. As far as is known, the DNA56862-1343 sequence encodes a novelfactor designated herein as PRO831; using the WU-BLAST2 sequencealignment computer program, no sequence identities to any known proteinswere revealed.

8. PRO1113

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1113 (shown in FIG. 16 and SEQ IDNO:24) has certain amino acid sequence identity with LIG-1 and SLIT.Accordingly, it is presently believed that PRO1113 disclosed in thepresent application is a newly identified member of the leucine richrepeat family and may possess protein-protein interaction activity as istypical of this family.

9. PRO1194

As far as is known, the DNA57841-1522 sequence encodes a novel factordesignated herein as PRO1194; using WU-BLAST2 sequence alignmentcomputer programs, limited sequence identities to known proteins wererevealed.

10. PRO1110

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1110 (shown in FIG. 20 andSEQ ID NO:31) has certain amino acid sequence identity with the murinemyeloid upregulated protein. Accordingly, it is presently believed thatPRO1110 disclosed in the present application is a newly identifiedmember of the myeloid upregulated protein family and may possessactivity typical of that family.

11. PRO1378

The DNA58730-1607 clone was isolated from a bone marrow library using atrapping technique which selects for nucleotide sequences encodingsecreted proteins. Thus, the DNA58730-1607 clone encodes a secretedfactor. As far as is known, the DNA58730-1607 sequence encodes a novelfactor designated herein as PRO1378. WU-BLAST2 sequence alignmentcomputer programs revealed some sequence identities between the aminoacid sequence of PRO1378 with known proteins. However, they weredetermined to not be significant.

12. PRO1481

As far as is known, the DNA58732-1650 sequence encodes a novel factordesignated herein as PRO1481. Using WU-BLAST2 sequence alignmentcomputer programs, only some sequence identities to known proteins wererevealed.

13. PRO1189

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1189 (shown in FIG. 26 and SEQ IDNO:43) has certain amino acid sequence identity with the amino acidsequence of an E25 protein designated “MUSE25A_(—)1” in the Dayboffdatabase. Accordingly, it is presently believed that PRO1189 disclosedin the present application is a newly identified member of the E25protein family and may possess activity or properties typical of thatfamily.

14. PRO1415

The DNA58852-1637 clone was isolated from a diseased human prostatetissue library using a trapping technique which selects for nucleotidesequences encoding secreted proteins. As far as is known, theDNA58852-1637 sequence encodes a novel factor designated herein asPRO1415; using the WU-BLAST2 sequence alignment computer program, nosignificant sequence identities to any known proteins were revealed.

15. PRO1411

As far as is known, the DNA59212-1627 sequence encodes a novel factordesignated herein as PRO1411. However, using WU-BLAST2 sequencealignment computer programs, some sequence identities to known proteinswere revealed.

16. PRO1295

As far as is known, the DNA59218-1559 sequence encodes a novel factordesignated herein as PRO1295. Using WU-BLAST2 sequence alignmentcomputer programs, only some sequence identities to known proteins wererevealed.

17. PRO1359

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1359 (shown in FIG. 34 and SEQ IDNO:56) has certain amino acid sequence identity withN-acetylgalactosamine alpha-2, 6-sialyltransferase. Accordingly, it ispresently believed that PRO1359 disclosed in the present application isa newly identified member of the sialyltransferase family and maypossess transferase activity typical of this family.

18. PRO1190

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1190 (shown in FIG. 36 and SEQ IDNO:58) has certain amino acid sequence identity with both rat and humanCDO. Accordingly, it is presently believed that PRO1190 disclosed in thepresent application is a newly identified member of the CDO family andmay possess cell adhesion activity typical of the CDO family.

19. PRO1772

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1772 (shownin FIG. 38 and SEQ ID NO:63) has certain amino acid sequence identitywith a human microsomal dipeptidase protein (P_R13857). Accordingly, itis presently believed that PRO1772 disclosed in the present applicationis a newly identified member of the peptidase protein family and maypossess activity typical of that protein family.

20. PRO1248

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1248 (shown in FIG. 40 andSEQ ID NO:68) has amino acid sequence identity with the PUT-2 protein(AF026198_(—)5). Accordingly, it is presently believed that PRO1248disclosed in the present application is a newly PUT-2 homolog and maypossess activity typical of the PUT-2 protein.

21. PRO1316

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1316 (shown in FIG. 42 and SEQ IDNO:70) has certain amino acid sequence identity with murine dickkopf.Accordingly, it is presently believed that PRO1316 disclosed in thepresent application is a newly identified member of the dickkopf familyand may possess the ability to cause head induction from the Spemannorganizer and/or Wnt antagonism.

22. PRO1197

As far as is known, the DNA60611-1524 sequence encodes a novel factordesignated herein as PRO1197. Using WU-BLAST2 sequence alignmentcomputer programs, only some sequence identities to known proteins wererevealed as further described in the examples.

23. PRO1293

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1293 (shown in FIG. 46 andSEQ ID NO:77) has certain amino acid sequence identity with the human Igheavy chain V region protein (HSVCD54_(—)1). Accordingly, it ispresently believed that PRO1293 disclosed in the present application isa newly identified member of the Ig superfamily of proteins andfragments thereof and may possess activity typical of that family.

24. PRO1380

The DNA60740-1615 clone was isolated from a human retina library. As faras is known, the DNA60740-1615 sequence encodes a novel multi-spantransmembrane polypeptide designated herein as PRO1380. Using WU-BLAST2sequence alignment computer programs, some sequence identity with knownproteins were revealed.

25. PRO1265

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1265 (shown in FIG. 50 and SEQ IDNO:84) has certain amino acid sequence identity with the FIG. 1polypeptide designated “MMU70429_(—)1” in the Dayhoff database (version35.45 SwissProt 35). Accordingly, it is presently believed that PRO1265disclosed in the present application is a newly identified member of theFIG. 1 family and may possess activity typical of the FIG. 1polypeptide, including activation by interleukin-4.

26. PRO1250

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1250 (shown in FIG. 52 andSEQ ID NO:86) has certain amino acid sequence identity with the humanlong chain fatty acid CoA ligase protein (LCFB_HUMAN). Accordingly, itis presently believed that PRO1250 disclosed in the present applicationis a newly identified long chain fatty acid CoA ligase homolog that mayhave activity typical of long chain fatty acis CoA ligase.

27. PRO1475

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1475 (shown in FIG. 54 andSEQ ID NO:88) has certain amino acid sequence identity with a portion ofthe mouse alpha-3-D-mannoside beat-1,2-N-acetylglucosaminyltransferase Iprotein. Accordingly, it is presently believed that PRO1475 disclosed inthe present application is a newly identified member of theN-acetylglucosaminyltransferase protein family and may possess activitytypical of that protein family.

28. PRO1377

As described herein, WU-BLAST2 sequence alignment computer programs wereused to determine the sequence identity of the PRO1377 amino acidsequence with the amino acid sequences of known proteins. While somesequence identities were revealed, they were determined to not besignificant. Accordingly, as far as is known, the DNA61608 sequenceencodes a novel transmembrane protein designated herein as PRO1377.

29. PRO1326

The DNA62808-1582 clone is believed to encode a secreted factor. As faras is known, the DNA62808-1582 sequence encodes a novel factordesignated herein as PRO1326; using WU-BLAST2 sequence alignmentcomputer programs, sequence identities to known proteins were revealedbut determined not to be significant.

30. PRO1249

The DNA62809-1531 clone was isolated from a human colon tumor tissuelibrary using a trapping technique which selects for nucleotidesequences encoding secreted proteins. As far as is known, theDNA62809-1531 sequence encodes a novel factor designated herein asPRO1249; using the WU-BLAST2 sequence alignment computer program, nosequence identities to any known proteins were revealed.

31. PRO1315

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1315 (shown in FIG. 62 andSEQ ID NO:104) has certain amino acid sequence identity with the classII cytokine receptor 4 protein of mus musculus (MMU53696_(—)1).Accordingly, it is presently believed that PRO1315 disclosed in thepresent application is a newly identified member of the cytokine reeptorprotein family and may possess activity typical of that family.

32. PRO1599

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1599 (shown in FIG. 64 and SEQ IDNO:111) has certain amino acid sequence identity with Dayhoff sequence“CFAD_PIG”. Accordingly, it is presently believed that PRO1599 disclosedin the present application is a newly identified member of the GranzymeM family and may possess activity or properties typical of the GranzymeM family.

33. PRO1430

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1430 (shown in FIG. 66 and SEQ IDNO:116) has certain amino acid sequence identity prostate specificreductase (designated “P_WO3198” in the Dayhoff database). Accordingly,it is presently believed that PRO1430 disclosed in the presentapplication is a newly identified member of the reductase family and maypossess activity typical of members of the reductase family.

34. PRO1374

As far as is known, the DNA64849-1604 sequence encodes a novel factordesignated herein as PRO1374; using WU-BLAST2 sequence alignmentcomputer programs, some sequence identities to known proteins such asthe human alpha subunit of P4HA were revealed. Therefore, it is believedthat PRO1374 is related to P4HA and may share one or more mechanisms.

35. PRO1311

The DNA64863-1573 clone was isolated from human aortic endothelial cellsand is believed to encode a novel transmembrane polypeptide designatedherein as PRO1311. Using WU-BLAST2 sequence alignment computer programs,some sequence identities with known proteins were revealed, but weredetermined to not be significant.

36. PRO1357

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1357 (shown in FIG. 72 andSEQ ID NO:128) has certain amino acid sequence identity with the vonEbner minor salivary gland protein of mus musculus (MMU46068_(—)1).Accordingly, it is presently believed that PRO1357 disclosed in thepresent application is a newly identified von Ebner minor salivary glandprotein homolog.

37. PRO1244

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1244 (shown in FIG. 74 and SEQ IDNO:130) has certain amino acid sequence identity with a knownimplantation-associated protein designated “AF008554_(—)1” on theDayhoff database (version 35.45 SwissProt 35). Accordingly, it ispresently believed that PRO1244 disclosed in the present application isa newly identified member of the implantation-associated protein familyand may possess attachment activity typical of that protein family.

38. PRO1246

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1246 (shown in FIG. 76 andSEQ ID NO:132) has certain amino acid sequence identity with the murinebone-related sulphatase-like precursor protein (P_R51355). Accordingly,it is presently believed that PRO1246 disclosed in the presentapplication is a newly identified bone-related sulphatase homolog andmay possess activity typical of bone-related sulfatase.

39. PRO1356

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1356 (shown in FIG. 78 andSEQ ID NO:134) has certain amino acid sequence identity with theCPE-receptor protein of mus musculus (AB000713_(—)1). Accordingly, it ispresently believed that PRO1356 disclosed in the present application isa newly identified member of the CPE receptor family and may possessactivity typical of that family.

40. PRO1275

As far as is known, the DNA64888-1542 sequence encodes a novel factordesignated herein as PRO1275. Using WU-BLAST2 sequence alignmentcomputer programs, some sequence identities to known proteins wererevealed.

41. PRO1274

As far as is known, the DNA64889-1541 sequence encodes a novel factordesignated herein as PRO1274. Using WU-BLAST2 sequence alignmentcomputer programs, some sequence identities to known proteins wererevealed.

42. PRO1412

The DNA64897-1628 clone is believed to be a secreted factor. As far asis known, the DNA64897-1628 sequence encodes a novel factor designatedherein as PRO1412; using WU-BLAST2 sequence alignment computer programs,sequence identities to known proteins were revealed but determined notto be significant.

43. PRO1557

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1557 (shown in FIG. 86; SEQ IDNO:142) has certain amino acid sequence identity chordin proteindesignated AF034606_(—)1 in the Dayhoff database. Accordingly, it ispresently believed that PRO1557 disclosed in the present application isa newly identified member of the chordin family and may possess activitytypical of the chordin family.

44. PRO1286

The DNA64903-1553 clone identified using techniques which selects fornucleotide sequences encoding secreted proteins. As far as is known, theDNA64903 sequence encodes a novel secreted factor designated herein asPRO1286. Using WU-BLAST2 sequence alignment computer programs, somesequence identities to known proteins were revealed; however, it wasdetermined that they were not significant.

45. PRO1294

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1294 (shown in FIG. 90 andSEQ ID NO:146) has certain amino acid sequence identity with theneuronal olfactomedin-related ER localized protein of the rat (173636).Accordingly, it is presently believed that PRO1294 disclosed in thepresent application is a newly identified olfactomedin homolog and maypossess activity typical of that protein.

46. PRO1347

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1347 (shown in FIG. 92 and SEQ IDNO:148) has certain amino acid sequence identity with butyrophilin.Moreover, there is a transmembrane domain approximately in the middle ofthe sequence as is typical of butyrophilins. Accordingly, it ispresently believed that PRO1347 disclosed in the present application isa newly identified member of the butyrophilin family and may play a rolein the budding and release of milk-fat glubules during lactation.

47. PRO1305

The DNA64952-1568 clone was isolated from a human fetal kidney libraryusing a trapping technique which selects for nucleotide sequencesencoding secreted proteins. Thus, the DNA64952-1568 clone does encode asecreted factor. As far as is known, the DNA64952-1568 sequence encodesa novel factor designated herein as PRO1305; using the WU-BLAST2sequence alignment computer program, no sequence identities to any knownproteins were revealed.

48. PRO1273

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1273 (shown in FIG. 96 and SEQ IDNO:158) has certain amino acid sequence identity with a lipocalinprecursor. Moreover. FIG. 96 shows that PRO1273 has a motif conserved inlipocalins. Accordingly, it is presently believed that PRO1273 disclosedin the present application is a newly identified member of the lipocalinfamily and shares at least one mechanism with lipocalins.

49. PRO1302

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1302 (shown in FIG. 98 and SEQ IDNO:160) has certain amino acid sequence identity with CD33L1 and CD33L2.Accordingly, it is presently believed that PRO1302 disclosed in thepresent application is a newly identified member of the sialoadhesinfamily and possesses characteristics typical of this family.Specifically, PRO1302 may be involved in cancer, inflammation,hemopoisis, neuronal development and/or immunity.

50. PRO1283

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1283 (shown in FIG. 100 andSEQ ID NO:162) has certain amino acid sequence identity with the ratodorant binding protein homolog OBP-II precursor (A40464). Accordingly,it is presently believed that PRO1283 disclosed in the presentapplication is a newly odorant binding protein and may possess activitytypical of the odorant binding proteins.

51. PRO1279

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1279 (shown in FIG. 102 andSEQ ID NO:170) has certain amino acid sequence identity with the mouseneuropsin protein (156559). Accordingly, it is presently believed thatPRO1279 disclosed in the present application is a newly identifiedneuropsin homolog and may possess activity typical of the neuropsinprotein.

52. PRO1304

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1304 (shown in FIG. 104 andSEQ ID NO:180) has certain amino acid sequence identity with the FK-506binding protein of mus musculus (AF040252_(—)1). Accordingly, it ispresently believed that PRO1304 disclosed in the present application isa newly identified member of the FK506 binding protein family and maypossess activity typical of that family.

53. PRO1317

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1317 (shown in FIG. 106 and SEQ IDNO:189) has certain amino acid sequence identity with human CD97protein. Accordingly, it is presently believed that PRO1317 disclosed inthe present application is a leukocyte antigen that may be involved inleukocyte activation.

54. PRO1303

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1303 (shown in FIG. 108 and SEQ IDNO:194) has certain amino acid sequence identity with neuropsin.Accordingly, it is presently believed that PRO1303 disclosed in thepresent application is a newly identified member of the serine proteasefamily and may possess catabolic activity typical of this family.

55. PRO1306

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1306 (shown in FIG. 110 and SEQ IDNO:196) has certain amino acid sequence identity with Dayhoff sequcnceno. AIF1_HUMAN. Accordingly, it is presently believed that PRO1306disclosed in the present application is a newly identified member of theAIF1/daintain family and may possess activity and properties typical ofAIF1/daintain.

56. PRO1336

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1336 (shown in FIG. 112 and SEQ IDNO:198) has certain amino acid sequence identity with slit. Accordingly,it is presently believed that PRO1336 disclosed in the presentapplication is a newly identified member of the EGF-repeat family andmay possess protein interaction mediation activity.

57. PRO1278

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1278 (shown in FIG. 114 and SEQ IDNO:203) has certain amino acid sequence identity lysozyme c-1 precursordesignated “LYC1_ANAPL” in the Dayhoff database. Accordingly, it ispresently believed that PRO1278 disclosed in the present application isa newly identified member of the lysozyme family and may possesshydrolytic and other activity typical of the lysozyme family.

58. PRO1298

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1298 (shown in FIG. 116 and SEQ IDNO:210) has certain amino acid sequence identity withglycosyltransferase alg2. Accordingly, it is presently believed thatPRO1298 disclosed in the present application is a newly identifiedmember of the glycosyltransferase family and may share at least onemechanism with members of this family.

59. PRO1301

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1301 (shown in FIG. 118 and SEQ IDNO:212) has consistent amino acid sequence identity with cytochrome P450proteins. Accordingly, it is presently believed that PRO1301 disclosedin the present application is a newly identified member of thecytochrome P450 family and may possess monooxygenase activity typical ofthe cytochrome P450 family.

60. PRO1268

As far as is known, the DNA66519-1535 sequence encodes a noveltransmembrane polypeptide factor designated herein as PRO1268. UsingWU-BLAST2 sequence alignment computer programs, sequence identity to aknown protein was revealed, but determined to not be significant.

61. PRO1269

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1269 (shown in FIG. 122 and SEQ IDNO:216) has certain amino acid sequence identity a bovine granulocytepeptide A precursor, designated “P_W23722” on the Dayhoff database(version 35.45 SwissProt 35). Accordingly, it is presently believed thatPRO1269 disclosed in the present application is a newly identifiedmember of the granulocyte A peptide family and may possess microbialactivity typical of that family of peptides.

62. PRO1327

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1327 (shown in FIG. 124 andSEQ ID NO:218) has certain amino acid sequence identity with the ratneurexophilin-1 protein (NPH1_RAT). Accordingly, it is presentlybelieved that PRO1327 disclosed in the present application is a newlyidentified member of the neurexophilin protein family and may possessactivity typical of that protein family.

63. PRO1382

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1382 (shown in FIG. 126 and SEQ IDNO:220) has certain amino acid sequence identity with the amino acidsequence of a known cerebellin-like glycoprotein designated “CERL_RAT”in the Dayhoff database. Accordingly, it is presently believed thatPRO1382 disclosed in the present application is a newly identifiedmember of the cerebellin family of neuropeptides and may possessactivity and properties typical of cerebellin.

64. PRO1328

The DNA66658-1584 clone was isolated from a human diseased prostatetissue library using a trapping technique which selects for nucleotidesequences encoding proteins. As far as is known, the DNA66658-1584sequence encodes a novel factor designated herein as PRO1328; using theWU-BLAST2 sequence alignment computer program, no significant sequenceidentities to any known proteins were revealed.

65. PRO1325

The DNA66659-1593 clone was isolated from a human thymus tissue libraryusing a trapping technique which selects for nucleotide sequencesencoding proteins. As far as is known, the DNA66659-1593 sequenceencodes a novel factor designated herein as PRO1325; using the WU-BLAST2sequence alignment computer program, no sequence identities to any knownproteins were revealed.

66. PRO1340

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1340 (shown in FIG. 132 and SEQ IDNO:229) has certain amino acid sequence identity with Dayhoff sequenceno. I46536. Accordingly, it is presently believed that PRO1340 disclosedin the present application is a newly identified member of the cadherinfamily and may possess activity and properties typical of the cadherinfamily.

67. PRO1339

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1339 (shown in FIG. 134 and SEQ IDNO:234) has certain amino acid sequence identity with human pancreaticcarboxypeptidase and carboxypeptidase a1. Accordingly, it is presentlybelieved that PRO1339 disclosed in the present application is a newlyidentified member of the carboxypeptidase family and possessescaboxypeptidase activity.

68. PRO1337

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1337 (shown in FIG. 136 and SEQ IDNO:236) has certain amino acid sequence identity with a human TBGidentified as “THBG_HUMAN” in the Dayhoff database. Accordingly, it ispresently believed that PRO1337 disclosed in the present application isa newly identified member of the TBG family and may possess thyroidhormone transport capability and have other

69. PRO1342

The DNA66674-1599 clone was isolated from human esophageal tissue. Asdescribed in further detail below, using WU-BLAST2 sequence alignmentcomputer programs, some sequence identities to known proteins wererevealed. The DNA66674-1599 clone appears to encode for a noveltransmembrane polypeptide.

70. PRO1343

The DNA66675-1587 clone was isolated from a human smooth muscle celltissue library using a trapping technique which selects for nucleotidesequences encoding secreted proteins. Thus, the DNA66675-1587 clone doesencode a secreted factor. As far as is known, the DNA66675-1587 sequenceencodes a novel factor designated herein as PRO1343; using the WU-BLAST2sequence alignment computer program, no significant sequence identitiesto any known proteins were revealed.

71. PRO1480

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1480 (shown in FIG. 142 and SEQ IDNO:253) has certain amino acid sequence identity with Dayhoff sequenceno. I48746. Accordingly, it is presently believed that PRO1480 disclosedin the present application is a newly identified member of theSemaphorin C family.

72. PRO1487

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1487 (FIG. 144; SEQ ID NO:260) hascertain amino acid sequence identity with a radical fringe proteindesignated GGU82088_(—)1 on the Dayhoff database. Accordingly, it ispresently believed that PRO1487 disclosed in the present application isa newly identified member of the fringe family and may possess activitytypical of the fringe family.

73. PRO1418

As far as is known, the DNA68864-1629 sequence encodes a novel factordesignated herein as PRO1418. Using WU-BLAST2 sequence alignmentcomputer programs, sequence identities to known proteins were minimal.

74. PRO1472

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1472 (shown in FIG. 148 and SEQ IDNO:267) has certain amino acid sequence identity with butyrophilin.Accordingly, it is presently believed that PRO1472 disclosed in thepresent application is a newly identified member of the butyrophilinfamily and may possess involvement in lactation.

75. PRO1461

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1461 (shown in FIG. 150 and SEQ IDNO:269) has certain amino acid sequence identity the trypsin-like enzymeidentified as “P_R89435” on the Dayhoff database. Accordingly, it ispresently believed that PRO1461 disclosed in the present application isa newly identified member of the serine protease family and may possessserine protease activity, and more particularly, may possess enzymaticactivity typical of other trypsin-like enzymes. Homology was also foundto exist between the PRO1461 amino acid sequence and other trypsin-likeenzymes and serine proteases in the Dayhoff database.

76. PRO1410

The DNA68874-1622 clone was isolated from a human brain meningiomatissue library using a trapping technique which selects for nucleotidesequences encoding proteins. As far as is known, the DNA68874-1622sequence encodes a novel factor designated herein as PRO1410; using theWU-BLAST2 sequence alignment computer program, no sequence identities toany known proteins were revealed.

77. PRO1568

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1568 (shown in FIG. 154 and SEQ IDNO:273) has certain amino acid sequence identity to tetraspan 5 andtetraspan 4. Accordingly, it is presently believed that PRO1568disclosed in the present application is a newly identified member of thetetraspanin family and may possess molecular facilitator activitytypical of this family.

78. PRO1570

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1570 (shown in FIG. 156 and SEQ IDNO:275) has certain amino acid sequence identity with SP60; however, forthe first time, the first 199 amino acids (or amino terminal end) ofthat protein are identified and presented herein. Accordingly, it ispresently believed that PRO1570 disclosed in the present application isa newly identified member of the serine protease family and is involvedin carcinoma.

79. PRO1317

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1317 (shown in FIG. 158 and SEQ IDNO:277) has certain amino acid sequence identity with a known semaphorinB protein, designated “I48745” on the Dayhoff database. Accordingly, itis presently believed that PRO1317 disclosed in the present applicationis a newly identified member of the semaphorin glycoprotein family andmay possess activity or properties typical of semaphorins.

80. PRO1780

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1780 (shown in FIG. 160 and SEQ IDNO:282) has certain amino acid sequence identity with a knownglucuronosyltransferase designated “UDA2_RABIT” in the Dayhoff database.Accordingly, it is presently believed that PRO1780 disclosed in thepresent application is a newly identified member of theglucuronosyltransferase family and may possess enzymatic activity andother properties typical of the glucuronosyltransferase family.

81. PRO1486

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1486 (shown in FIG. 162 and SEQ IDNO:287) has certain amino acid sequence identity with cerebellin 1precursor. Accordingly, it is presently believed that PRO1486 disclosedin the present application is a newly identified member of thecerebellin family and shares at least one mechanism with cerebellin.

82. PRO1433

The DNA71184-1634 clone was isolated from a human adrenal gland tissuelibrary using a trapping technique which selects for nucleotidesequences encoding proteins. As far as is known, the DNA71184-1634sequence encodes a novel factor designated herein as PRO1433; using theWU-BLAST2 sequence alignment computer program, no sequence identities toany known proteins were revealed.

83. PRO1490

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1490 (shownin FIG. 166 and SEQ ID NO:297) has certain amino acid sequence identitywith a portion of the 1-acyl-sn-glycerol-3-phosphate acyltransferaseprotein (S60478). Accordingly, it is presently believed that PRO1490disclosed in the present application is a newly identified member of theacyltransferase protein family and may possess activity typical of1-acyl-sn-glycerol-3-phosphate acyltransferase proteins.

84. PRO1482

The DNA71234-1651 clone was isolated from a human adrenal gland libraryusing a trapping technique which selects for nucleotide sequencesencoding secreted proteins. Thus, the DNA71234-1651 clone does encode asecreted factor. As far as is known, the DNA71234-1651 sequence encodesa novel factor designated herein as PRO1482; using the WU-BLAST2sequence alignment computer program, no sequence identities to any knownproteins were revealed.

85. PRO1446

As far as is known, the DNA71277-1636 sequence encodes a novel factordesignated herein as PRO1446. Using WU-BLAST2 sequence alignmentcomputer programs, minimal sequence identities to known proteins wererevealed.

86. PRO1558

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1558 (shown in FIG. 172 andSEQ ID NO:306) has significant amino acid sequence identity with amethyltransferase protein (CAMT EUCGU). Accordingly, it is presentlybelieved that PRO1558 disclosed in the present application is a newlyidentified member of the methyltransferase protein family and maypossess activity typical of that protein family.

87. PRO1604

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1604 (shown in FIG. 174 and SEQ IDNO:308) has certain amino acid sequence identity with the mouse livercancer-originated cell growth factor designated P_W37483 on the Dayhoffdatabase. Accordingly, it is presently believed that PRO1604 disclosedin the present application is a newly identified member of the HDGFfamily and may possess growth factor activity typical of other HDGFs.

88. PRO1491

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1491 (shownin FIG. 176 and SEQ ID NO:310) has certain amino acid sequence identitywith a portion of the collapsin-2 protein of Gallus gallus(GGU28240_(—)1). Accordingly, it is presently believed that PRO1491disclosed in the present application is a newly identified member of thecollapsin protein family and may possess activity typical of thatprotein family.

89. PRO1431

It has been found that the full-length native sequence PRO1431 [shown inFIG. 178 (SEQ ID NO:315) has significant sequence identity with the SH3domain containing protein SH17_HUMAN. Accordingly, it is presentlybelieved that PRO1431 disclosed in the present application is a newlyidentified member of proteins having an SH3 domains and may possesssignal transduction properties.

90. PRO1563

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of a full-length native sequence PRO1563 (shown inFIG. 180 and SEQ ID NO:317) has certain amino acid sequence identitywith a portion of the mouse ADAMTS-1 protein (AB001735_(—)1).Accordingly, it is presently believed that PRO1563 disclosed in thepresent application is a newly identified member of the ADAM proteinfamily and may possess activity typical of that protein family.

91. PRO1565

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1565 (shownin FIG. 182 and SEQ ID NO:322) has certain amino acid sequence identitywith a portion of the chondromodulin-I protein of rattus norvegicus(AF051425_(—)1). Accordingly, it is presently believed that PRO1565disclosed in the present application is a newly identified member of thechondromodulin protein family and may possess activity typical of thatprotein family.

92. PRO1571

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1571 (shownin FIG. 184 and SEQ ID NO:324) has certain amino acid sequence identitywith a portion of the human clostridium perfringens enterotoxin receptorprotein (AB000712_(—)1). Accordingly, it is presently believed thatPRO1571 disclosed in the present application is a newly identified CPE-Rhomolog and may possess activity typical of the CPE-R protein.

93. PRO1572

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1572 (shown in FIG. 186 and SEQ IDNO:326) has certain amino acid sequence identity with CPE-R.Accordingly, it is presently believed that PRO1572 disclosed in thepresent application is related to CPE-R and may possess at least oneshared mechanism.

94. PRO1573

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1573 (shown in FIG. 188 and SEQ IDNO:328) has certain amino acid sequence identity with CPE-R.Accordingly, it is presently believed that PRO1573 disclosed in thepresent application is related to CPE-R and may possesses at least oneshared mechanism.

95. PRO1488

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1488 (FIG. 190; SEQ ID NO:330) hascertain amino acid sequence identity with a known CPE-R designated“AB000712_(—)1” on the Dayhoff database. Accordingly, it is presentlybelieved that PRO1488 disclosed in the present application is a newlyidentified member of the CPE-R family and may possess binding activitytypical of the CPE-R family.

96. PRO1489

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1489 (shownin FIG. 192 and SEQ ID NO:332) has certain amino acid sequence identitywith the clostridium perfringens enterotoxin receptor of Cercopithecusaethiops (D88492_(—)1). Accordingly, it is presently believed thatPRO1489 disclosed in the present application is a newly identifiedclostridium perfringens enterotoxin receptor homolog and may possessactivity typical of the clostridium perfringens enterotoxin receptorprotein.

97. PRO1474

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1474 (shown in FIG. 194 and SEQ IDNO:334) has certain amino acid sequence identity with ovomucoid.Accordingly, it is presently believed that PRO1474 disclosed in thepresent application is a newly identified member of the kazal serineprotease inhibitor family and may possess serine protease inhibitoryactivity typical of this family.

98. PRO1508

The DNA73742-1508 clone was isolated from a human diseased cartilagetissue library. As far as is known, the DNA73742-1508 sequence encodes anovel factor designated herein as PRO1508; although, using WU-BLAST2sequence alignment computer programs, some sequence identities to knownproteins were revealed.

99. PRO1555

The DNA73744-1665 clone was isolated from a human tissue library. As faras is known, the DNA73744 sequence encodes a novel transmembrane proteindesignated herein as PRO1555. Using WU-BLAST2 sequence alignmentcomputer programs, some sequence identities to known proteins wererevealed.

100. PRO1485

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1485 (shown in FIG. 200 and SEQ IDNO:340) has certain amino acid sequence identity with lysozyme Cprecursor peptide. Accordingly, it is presently believed that PRO1485disclosed in the present application is a newly identified member of thelysozyme family and shares at least one like mechanism.

101. PRO1564

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of a full-length native sequence PRO1564 (shown inFIG. 202 and SEQ ID NO:347) has certain amino acid sequence identitywith a portion of a mouse polypeptide GalNAc transferase T4 protein(MMU73819_(—)1). Accordingly, it is presently believed that PRO1564disclosed in the present application is a newly identified member of theN-acetylgalactosaminyltransferase protein family and may possessactivity typical of that protein family.

102. PRO1755

As far as is known, the DNA76396-1698 sequence encodes a noveltransmembrane protein designated herein as PRO1755. Although, somesequence identities to known proteins was revealed using WU-BLAST2sequence alignment computer programs.

103. PRO1757

The DNA76398-1699 clone was isolated from a human testicular tissuelibrary using a trapping technique which selects for nucleotidesequences encoding proteins. As far as is known, the DNA76398-1699sequence encodes a novel factor designated herein as PRO1757; using theWU-BLAST2 sequence alignment computer program, no significant sequenceidentities to any known proteins were revealed.

104. PRO1758

The DNA76399-1700 clone was isolated from a library derived from humanthymus tissue obtained from a fetus that died at 17 weeks' gestationfrom anencephalus. It is believed that the DNA76399-1700 clone encodes anovel secreted factor, designated herein as PRO1758. Using WU-BLAST2sequence alignment computer programs, significant sequence identity wasrevealed between the amino acid sequences of PRO1758 and Dayhoffsequence No. AC005328_(—)2.

105. PRO1575

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1575 (shown in FIG. 210 and SEQ IDNO:358) has certain amino acid sequence identity with Dayhoff sequenceno. A12005_(—)1. Accordingly, it is presently believed that PRO1575disclosed in the present application is a newly identified member of theprotein disulfide isomerase family and may possess activity andproperties typical of the disulfide isomerase family.

106. PRO1787

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1787 (shown in FIG. 212 and SEQ IDNO:364) has certain amino acid sequence identity with various species ofmyelin p0. Accordingly, it is presently believed that PRO1787 disclosedin the present application is a newly identified member of the myelin p0protein family and may share at least one similar mechanism. It isbelieved that modulators of PRO1787 may be used to treat myelin p0associated disorders, such as neuropathy, hereditary tooth disease, etc.

107. PRO1781

Using WU-BLAST2 sequence alignment computer programs, some sequenceidentities were found between the PRO1781 amino acid sequence (SEQ IDNO:366) and the amino acid sequences of known proteins, but were notfound to be significant. Accordingly, as far as is known, theDNA76522-2500 sequence encodes a novel protein.

108. PRO1556

The DNA76529-1666 clone was isolated from a human breast tumor tissuelibrary. As far as is known, the DNA76529-1666 sequence encodes a noveltransmembrane protein designated herein as PRO1556. Using WU-BLAST2sequence alignment computer programs, some sequence identities to knownproteins were revealed.

109. PRO1759

As far as is known, the DNA76531-1701 sequence encodes a novel factordesignated herein as PRO1759; using WU-BLAST2 sequence alignmentcomputer programs, limited sequence identities to known proteins wererevealed.

110. PRO1760

As far as is known, the DNA76532-1702 sequence encodes a novel factordesignated herein as PRO1760; using WU-BLAST2 sequence alignmentcomputer programs, limited sequence identities to known proteins wererevealed.

111. PRO1561

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of a full-length native sequence PRO1561 (shown inFIG. 222 and SEQ ID NO:378) has certain amino acid sequence identitywith a portion of the human phospholipase A2 protein (P_R63053).Accordingly, it is presently believed that PRO1561 disclosed in thepresent application is a newly identified member of the phospholipase A2protein family and may possess activity typical of that protein family.

112. PRO1567

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1567 (FIG. 224; SEQ ID NO:383) hascertain amino acid sequence identity with human colon specific gene CSG6polypeptide, identified as P_WO6549 on the Dayhoff database.Accordingly, it is presently believed that PRO1567 disclosed in thepresent application is a newly identified CSG expression product, andmay possess properties typical of such proteins.

113. PRO1693

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1693 (shownin FIG. 226 and SEQ ID NO:385) has certain amino acid sequence identitywith a portion of a mouse insulin-like growth factor binding protein(ALS_MOUSE). Accordingly, it is presently believed that PRO1693disclosed in the present application is a newly identified member of theinsulin-like growth factor binding protein family and may possessactivity typical of that protein family.

114. PRO1784

As far as is known, the DNA77303-2502 sequence encodes a novel factordesignated herein as PRO1784; using WU-BLAST2 sequence alignmentcomputer programs, some sequence identities to known proteins wererevealed.

115. PRO1605

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1605 (shownin FIG. 230 and SEQ ID NO:395) has certain amino acid sequence identitywith a portion of the human alpha-1,3-mannosylglycoproteinbeta-1,6-n-acetyltransferase protein (GNT5_HUMAN). Accordingly, it ispresently believed that PRO1605 disclosed in the present application isa newly identified member of the glycosyltransferase protein family andmay possess activity typical of that protein family.

116. PRO1788

Using WU-BLAST2 sequence alignment computer programs, it has been foundthat a full-length native sequence PRO1788 (shown in FIG. 232 and SEQ IDNO:397) has certain amino acid sequence identity with Dayhoff sequence“GARP_HUMAN”, a leucine-rich repeat-containing protein encoded by a genelocalized in the 11q14 chromosomal region. Accordingly, it is presentlybelieved that PRO1788 disclosed in the present application is a newlyidentified member of the leucine-rich repeat-containing family and maypossess activity or properties typical of the leucine-richrepeat-containing family.

117. PRO1801

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a portion of the full-length native sequence PRO1801 (shownin FIG. 234 and SEQ ID NO:402) has certain amino acid sequence identitywith a portion of the IL-19 protein (P_W37935). Accordingly, it ispresently believed that PRO1801 disclosed in the present application isa newly identified member of the IL-10-related cytokine family and maypossess activity typical of that cytokine family.

118. UCP4

Using the Megalign DNASTAR computer program (and algorithms andparameters in this software set by the manufacturer) (Oxford MolecularGroup, Inc.), it has been found that a full-length native sequence UCP4(shown in FIG. 236 and SEQ ID NO:406) has certain amino acid sequenceidentity with UCP3, UCP2 and UCP1. Accordingly, it is presently believedthat UCP4 disclosed in the present application is a newly identifiedmember of the human uncoupling protein family and may possessactivity(s) and/or property(s) typical of that protein family, such asthe ability to enhance or supress metabolic rate by affectingmitochondrial membrane potential.

119. PRO193

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO193. In particular, Applicants have identified and isolated cDNAencoding a PRO193 polypeptide, as disclosed in further detail in theExamples below. The PRO193-encoding clone was isolated from a humanretina library.

120. PRO1130

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1130 (shown in FIG. 240 andSEQ ID NO:415) has amino acid sequence identity with the human 2-19protein. Accordingly, it is presently believed that PRO1130 disclosed inthe present application is a newly identified 2-19 protein homolog.

121. PRO1335

Using the WU-BLAST2 sequence alignment computer program, it has beenfound that a full-length native sequence PRO1335 (shown in FIG. 242 andSEQ ID NO:423) has certain amino acid sequence identity with the humancarbonic anhydrase precursor protein (AF037335_(—)1). Accordingly, it ispresently believed that PRO1335 disclosed in the present application isa newly identified member of the carbonic anhydrase protein family andmay possess activity typical of that family.

122. PRO1329

The DNA66660-1585 clone is believed to encode a secreted factor. As faras is known, the DNA66660-1585 sequence encodes a novel factordesignated herein as PRO1329; using WU-BLAST2 sequence alignmentcomputer programs, sequence identities to known proteins were revealedbut determined not to be significant.

123, PRO1550

The DNA76393-1664 clone was isolated from a subtracted human breasttumor tissue library. As far as is known, the DNA76393-1664 sequenceencodes a novel factor designated herein as PRO1550; using WU-BLAST2sequence alignment computer programs, sequence identities to knownproteins were revealed but determined not to be significant.

B. PRO Variants

In addition to the full-length native sequence PRO polypeptidesdescribed herein, it is contemplated that PRO variants can be prepared.PRO variants can be prepared by introducing appropriate nucleotidechanges into the PRO DNA, and/or by synthesis of the desired PROpolypeptide. Those skilled in the art will appreciate that amino acidchanges may alter post-translational processes of the PRO, such aschanging the number or position of glycosylation sites or altering themembrane anchoring characteristics.

Variations in the native full-length sequence PRO or in various domainsof the PRO described herein, can be made, for example, using any of thetechniques and guidelines for conservative and non-conservativemutations set forth, for instance, in U.S. Pat. No. 5,364,934.Variations may be a substitution, deletion or insertion of one or morecodons encoding the PRO that results in a change in the amino acidsequence of the PRO as compared with the native sequence PRO. Optionallythe variation is by substitution of at least one amino acid with anyother amino acid in one or more of the domains of the PRO. Guidance indetermining which amino acid residue may be inserted, substituted ordeleted without adversely affecting the desired activity may be found bycomparing the sequence of the PRO with that of homologous known proteinmolecules and minimizing the number of amino acid sequence changes madein regions of high homology. Amino acid substitutions can be the resultof replacing one amino acid with another amino acid having similarstructural and/or chemical properties, such as the replacement of aleucine with a serine, i.e., conservative amino acid replacements.Insertions or deletions may optionally be in the range of about 1 to 5amino acids. The variation allowed may be determined by systematicallymaking insertions, deletions or substitutions of amino acids in thesequence and testing the resulting variants for activity exhibited bythe full-length or mature native sequence.

PRO polypeptide fragments are provided herein. Such fragments may betruncated at the N-terminus or C-terminus, or may lack internalresidues, for example, when compared with a full length native protein.Certain fragments lack amino acid residues that are not essential for adesired biological activity of the PRO polypeptide.

PRO fragments may be prepared by any of a number of conventionaltechniques. Desired peptide fragments may be chemically synthesized. Analternative approach involves generating PRO fragments by enzymaticdigestion, e.g., by treating the protein with an enzyme known to cleaveproteins at sites defined by particular amino acid residues, or bydigesting the DNA with suitable restriction enzymes and isolating thedesired fragment. Yet another suitable technique involves isolating andamplifying a DNA fragment encoding a desired polypeptide fragment, bypolymerase chain reaction (PCR). Oligonucleotides that define thedesired termini of the DNA fragment are employed at the 5′ and 3′primers in the PCR. Preferably, PRO polypeptide fragments share at leastone biological and/or immunological activity with the native PROpolypeptide disclosed herein.

In particular embodiments, conservative substitutions of interest areshown in Table 6 under the heading of preferred substitutions. If suchsubstitutions result in a change in biological activity, then moresubstantial changes, denominated exemplary substitutions in Table 6, oras further described below in reference to amino acid classes, areintroduced and the products screened.

TABLE 6 Original Exemplary Preferred Residue Substitutions SubstitutionsAla (A) val; leu; ile val Arg (R) lys; gln; asn lys Asn (N) gln; his;lys; arg gln Asp (D) glu glu Cys (C) ser ser Gln (Q) asn asn Glu (E) aspasp Gly (G) pro; ala ala His (H) asn; gln; lys; arg arg Ile (I) leu;val; met; ala; phe; leu norleucine Leu (L) norleucine; ile; val; ilemet; ala; phe Lys (K) arg; gln; asn arg Met (M) leu; phe; ile leu Phe(F) leu; val; ile; ala; tyr leu Pro (P) ala ala Ser (S) thr thr Thr (T)ser ser Trp (W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile;leu; met; phe; ile ala; norleucine

Substantial modifications in function or immunological identity of thePRO polypeptide are accomplished by selecting substitutions that differsignificantly in their effect on maintaining (a) the structure of thepolypeptide backbone in the area of the substitution, for example, as asheet or helical conformation, (b) the charge or hydrophobicity of themolecule at the target site, or (c) the bulk of the side chain.Naturally occurring residues are divided into groups based on commonside-chain properties:

-   (1) hydrophobic: norleucine, met, ala, val, leu, ile;-   (2) neutral hydrophilic: cys, ser, thr;-   (3) acidic: asp, glu;-   (4) basic: asn, gin, his, lys, arg;-   (5) residues that influence chain orientation: gly, pro; and-   (6) aromatic: trp, tyr, phe.

Non-conservative substitutions will entail exchanging a member of one ofthese classes for another class. Such substituted residues also may beintroduced into the conservative substitution sites or, more preferably,into the remaining (non-conserved) sites.

The variations can be made using methods known in the art such asoligonucleotide-mediated (site-directed) mutagenesis, alanine scanning,and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl.Acids Res., 13: 4331 (1986); Zoller et al., Nucl. Acids Res., 10: 6487(1987)], cassette mutagenesis [Wells et al., Gene, 34: 315 (1985)],restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc.London SerA, 317: 415 (1986)] or other known techniques can be performedon the cloned DNA to produce the PRO variant DNA.

Scanning amino acid analysis can also be employed to identify one ormore amino acids along a contiguous sequence. Among the preferredscanning amino acids are relatively small, neutral amino acids. Suchamino acids include alanine, glycine, serine, and cysteine. Alanine istypically a preferred scanning amino acid among this group because iteliminates the side-chain beyond the beta-carbon and is less likely toalter the main-chain conformation of the variant [Cunningham and Wells,Science, 244: 1081-1085 (1989)]. Alanine is also typically preferredbecause it is the most common amino acid. Further, it is frequentlyfound in both buried and exposed positions [Creighton, The Proteins,(W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150: 1 (1976)]. Ifalanine substitution does not yield adequate amounts of variant, anisoteric amino acid can be used.

C. Modifications of PRO

Covalent modifications of PRO are included within the scope of thisinvention. One type of covalent modification includes reacting targetedamino acid residues of a PRO polypeptide with an organic derivatizingagent that is capable of reacting with selected side chains or the N- orC-terminal residues of the PRO. Derivatization with bifunctional agentsis useful, for instance, for crosslinking PRO to a water-insolublesupport matrix or surface for use in the method for purifying anti-PROantibodies, and vice-versa. Commonly used crosslinking agents include,e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde,N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylicacid, homobifunctional imidoesters, including disuccinimidyl esters suchas 3,3′-dithiobis(succinimidylpropionate), bifunctional maleimides suchas bis-N-maleimido-1,8-octane and agents such asmethyl-3-[(p-azidophenyl)dithio]propioimidate.

Other modifications include deamidation of glutaminyl and asparaginylresidues to the corresponding glutamyl and aspartyl residues,respectively, hydroxylation of proline and lysine, phosphorylation ofhydroxyl groups of seryl or threonyl residues, methylation of theα-amino groups of lysine, arginine, and histidine side chains [T. E.Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman &Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminalamine, and amidation of any C-terminal carboxyl group.

Another type of covalent modification of the PRO polypeptide includedwithin the scope of this invention comprises altering the nativeglycosylation pattern of the polypeptide. “Altering the nativeglycosylation pattern” is intended for purposes herein to mean deletingone or more carbohydrate moieties found in native sequence PRO (eitherby removing the underlying glycosylation site or by deleting theglycosylation by chemical and/or enzymatic means), and/or adding one ormore glycosylation sites that are not present in the native sequencePRO. In addition, the phrase includes qualitative changes in theglycosylation of the native proteins, involving a change in the natureand proportions of the various carbohydrate moieties present.

Addition of glycosylation sites to the PRO polypeptide may beaccomplished by altering the amino acid sequence. The alteration may bemade, for example, by the addition of, or substitution by, one or moreserine or threonine residues to the native sequence PRO (for O-linkedglycosylation sites). The PRO amino acid sequence may optionally bealtered through changes at the DNA level, particularly by mutating theDNA encoding the PRO polypeptide at preselected bases such that codonsare generated that will translate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties on thePRO polypeptide is by chemical or enzymatic coupling of glycosides tothe polypeptide. Such methods are described in the art, e.g., in WO87/05330 published 11 Sep. 1987, and in Aplin and Wriston, CRC Crit.Rev. Biochem., pp. 259-306 (1981).

Removal of carbohydrate moieties present on the PRO polypeptide may beaccomplished chemically or enzymatically or by mutational substitutionof codons encoding for amino acid residues that serve as targets forglycosylation. Chemical deglycosylation techniques are known in the artand described, for instance, by Hakimuddin, et al., Arch. Biochem.Biophys., 259: 52 (1987) and by Edge et al., Anal. Biochem., 118: 131(1981). Enzymatic cleavage of carbohydrate moieties on polypeptides canbe achieved by the use of a variety of endo- and exo-glycosidases asdescribed by Thotakura et al., Meth. Enzymol., 138: 350 (1987).

Another type of covalent modification of PRO comprises linking the PROpolypeptide to one of a variety of nonproteinaceous polymers, e.g.,polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, inthe manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144;4,670,417; 4,791,192 or 4,179,337.

The PRO of the present invention may also be modified in a way to form achimeric molecule comprising PRO fused to another, heterologouspolypeptide or amino acid sequence.

In one embodiment, such a chimeric molecule comprises a fusion of thePRO with a tag polypeptide which provides an epitope to which ananti-tag antibody can selectively bind. The epitope tag is generallyplaced at the amino- or carboxyl-terminus of the PRO. The presence ofsuch epitope-tagged forms of the PRO can be detected using an antibodyagainst the tag polypeptide. Also, provision of the epitope tag enablesthe PRO to be readily purified by affinity purification using ananti-tag antibody or another type of affinity matrix that binds to theepitope tag. Various tag polypeptides and their respective antibodiesare well known in the art. Examples include poly-histidine (poly-his) orpoly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptideand its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8: 2159-2165(1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10antibodies thereto [Evan et al., Molecular and Cellular Biology, 5:3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD) tagand its antibody [Paborsky et al., Protein Engineering, 3(6): 547-553(1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al.,BioTechnology, 6: 1204-1210 (1988)]; the KT3 epitope peptide [Martin etal., Science, 255: 192-194 (1992)]; an α-tubulin epitope peptide[Skinner et al., J. Biol. Chem., 266: 15163-15166 (1991)]; and the T7gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad.Sci. USA, 87: 6393-6397 (1990)].

In an alternative embodiment, the chimeric molecule may comprise afusion of the PRO with an immunoglobulin or a particular region of animmunoglobulin. For a bivalent form of the chimeric molecule (alsoreferred to as an “immunoadhesin”), such a fusion could be to the Feregion of an IgG molecule. The Ig fusions preferably include thesubstitution of a soluble (transmembrane domain deleted or inactivated)form of a PRO polypeptide in place of at least one variable regionwithin an Ig molecule. In a particularly preferred embodiment, theimmunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge,CH1, CH2 and CH3 regions of an IgG1 molecule. For the production ofimmunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27,1995.

D. Preparation of PRO

The description below relates primarily to production of PRO byculturing cells transformed or transfected with a vector containing PROnucleic acid. It is, of course, contemplated that alternative methods,which are well known in the art, may be employed to prepare PRO. Forinstance, the PRO sequence, or portions thereof, may be produced bydirect peptide synthesis using solid-phase techniques [see, e.g.,Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., SanFrancisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85: 2149-2154(1963)]. In vitro protein synthesis may be performed using manualtechniques or by automation. Automated synthesis may be accomplished,for instance, using an Applied Biosystems Peptide Synthesizer (FosterCity, Calif.) using manufacturer's instructions. Various portions of thePRO may be chemically synthesized separately and combined using chemicalor enzymatic methods to produce the full-length PRO.

1. Isolation of DNA Encoding PRO

DNA encoding PRO may be obtained from a cDNA library prepared fromtissue believed to possess the PRO mRNA and to express it at adetectable level. Accordingly, human PRO DNA can be convenientlyobtained from a cDNA library prepared from human tissue, such asdescribed in the Examples. The PRO-encoding gene may also be obtainedfrom a genomic library or by known synthetic procedures (e.g., automatednucleic acid synthesis).

Libraries can be screened with probes (such as antibodies to the PRO oroligonucleotides of at least about 20-80 bases) designed to identify thegene of interest or the protein encoded by it. Screening the cDNA orgenomic library with the selected probe may be conducted using standardprocedures, such as described in Sambrook et al., Molecular Cloning: ALaboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989).An alternative means to isolate the gene encoding PRO is to use PCRmethodology [Sambrook et al., supra: Dieffenbach et al. PCR Primer: ALaboratory Manual (Cold Spring Harbor Laboratory Press, 1995)].

The Examples below describe techniques for screening a cDNA library. Theoligonucleotide sequences selected as probes should be of sufficientlength and sufficiently unambiguous that false positives are minimized.The oligonucleotide is preferably labeled such that it can be detectedupon hybridization to DNA in the library being screened. Methods oflabeling are well known in the art, and include the use of radiolabelslike ³²P-labeled ATP, biotinylation or enzyme labeling. Hybridizationconditions, including moderate stringency and high stringency, areprovided in Sambrook et al., supra.

Sequences identified in such library screening methods can be comparedand aligned to other known sequences deposited and available in publicdatabases such as GenBank or other private sequence databases. Sequenceidentity (at either the amino acid or nucleotide level) within definedregions of the molecule or across the full-length sequence can bedetermined using methods known in the art and as described herein.

Nucleic acid having protein coding sequence may be obtained by screeningselected cDNA or genomic libraries using the deduced amino acid sequencedisclosed herein for the first time, and, if necessary, usingconventional primer extension procedures as described in Sambrook etal., supra, to detect precursors and processing intermediates of mRNAthat may not have been reverse-transcribed into cDNA.

2. Selection and Transformation of Host Cells

Host cells are transfected or transformed with expression or cloningvectors described herein for PRO production and cultured in conventionalnutrient media modified as appropriate for inducing promoters, selectingtransformants, or amplifying the genes encoding the desired sequences.The culture conditions, such as media, temperature, pH and the like, canbe selected by the skilled artisan without undue experimentation. Ingeneral, principles, protocols, and practical techniques for maximizingthe productivity of cell cultures can be found in Mammalian CellBiotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991)and Sambrook et al., supra.

Methods of eukaryotic cell transfection and prokaryotic celltransformation are known to the ordinarily skilled artisan, for example,CaCl₂, CaPO₄, liposome-mediated and electroporation. Depending on thehost cell used, transformation is performed using standard techniquesappropriate to such cells. The calcium treatment employing calciumchloride, as described in Sambrook et al., supra, or electroporation isgenerally used for prokaryotes. Infection with Agrobacterium tumefaciensis used for transformation of certain plant cells, as described by Shawet al., Gene, 23: 315 (1983) and WO 89/05859 published 29 Jun. 1989. Formammalian cells without such cell walls, the calcium phosphateprecipitation method of Graham and van der Eb, Virology, 52: 456-457(1978) can be employed. General aspects of mammalian cell host systemtransfections have been described in U.S. Pat. No. 4,399,216.Transformations into yeast are typically carried out according to themethod of Van Solingen et al., J. Bact., 130: 946 (1977) and Hsiao etal., Proc. Natl. Acad. Sci. (USA), 76: 3829 (1979). However, othermethods for introducing DNA into cells, such as by nuclearmicroinjection, electroporation, bacterial protoplast fusion with intactcells, or polycations, e.g., polybrene, polyornithine, may also be used.For various techniques for transforming mammalian cells, see Keown etal., Methods in Enzymology, 185: 527-537 (1990) and Mansour et al.,Nature, 336: 348-352 (1988).

Suitable host cells for cloning or expressing the DNA in the vectorsherein include prokaryote, yeast, or higher eukaryote cells. Suitableprokaryotes include but are not limited to eubacteria, such asGram-negative or Gram-positive organisms, for example,Enterobacteriaceae such as E. coli. Various E. coli strains are publiclyavailable, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776(ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC53,635). Other suitable prokaryotic host cells includeEnterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter,Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium,Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacillisuch as B. subtilis and B. licheniformis (e.g., B. licheniformis 41Pdisclosed in DD 266,710 published 12 Apr. 1989), Pseudomonas such as P.aeruginosa, and Streptomyces. These examples are illustrative ratherthan limiting. Strain W3110 is one particularly preferred host or parenthost because it is a common host strain for recombinant DNA productfermentations. Preferably, the host cell secretes minimal amounts ofproteolytic enzymes. For example, strain W3110 may be modified to effecta genetic mutation in the genes encoding proteins endogenous to thehost, with examples of such hosts including E. coli W3110 strain 1A2,which has the complete genotype tonA; E. coli W3110 strain 9E4, whichhas the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC55,244), which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT kan′; E. coli W3110 strain 37D6, which has the completegenotype tonA ptr3 phoA E15 (argF-lac) 169 degP oinpT rbs7 ilvG kan′; E.coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycinresistant degP deletion mutation; and an E. coli strain having mutantperiplasmic protease disclosed in U.S. Pat. No. 4,946,783 issued 7 Aug.1990. Alternatively, in vitro methods of cloning, e.g., PCR or othernucleic acid polymerase reactions, are suitable.

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are suitable cloning or expression hosts for PRO-encodingvectors. Saccharomyces cerevisiae is a commonly used lower eukaryotichost microorganism. Others include Schizosaccharomyces pombe (Beach andNurse, Nature, 290: 140 [1981]; EP 139,383 published 2 May 1985);Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al.,Bio/Technology, 9: 968-975 (1991)) such as, e.g., K. lactis (MW98-8C,CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 154(2): 737-742[1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K.wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum(ATCC 36,906; Van den Berg et al., Bio/Technology, 8: 135 (1990)), K.thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris(EP 183,070; Sreekrishna et al., J. Basic Microbiol, 28: 265-278[1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa(Case et al., Proc. Natl. Acad. Sci. USA, 76: 5259-5263 [1979]);Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published31 Oct. 1990); and filamentous fungi such as, e.g., Neurospora,Penicillium, Tolypocladium (WO 91/00357 published 10 Jan. 1991), andAspergillus hosts such as A. nidulans (Ballance et al., Biochem.Biophys. Res. Commun., 112: 284-289 [1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81: 1470-1474[1984]) and A. niger(Kelly and Hynes, EMBO J., 4: 475-479 [1985]).Methylotropic yeasts are suitable herein and include, but are notlimited to, yeast capable of growth on methanol selected from the generaconsisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces,Torulopsis, and Rhodotorula. A list of specific species that areexemplary of this class of yeasts may be found in C. Anthony, TheBiochemistry of Methylotrophs, 269 (1982).

Suitable host cells for the expression of glycosylated PRO arc derivedfrom multicellular organisms. Examples of invertebrate cells includeinsect cells such as Drosophila S2 and Spodoptera Sf9, as well as plantcells. Examples of useful mammalian host cell lines include Chinesehamster ovary (CHO) and COS cells. More specific examples include monkeykidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); humanembryonic kidney line (293 or 293 cells subcloned for growth insuspension culture, Graham et al., J. Gen Virol., 36: 59 (1977));Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl.Acad. Sci. USA, 77: 4216 (1980)); mouse sertoli cells (TM4, Mather,Biol. Reprod., 23: 243-251 (1980)); human lung cells (W138, ATCC CCL75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT060562, ATCC CCL51). The selection of the appropriate host cell isdeemed to be within the skill in the art.

3. Selection and Use of a Replicable Vector

The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may beinserted into a replicable vector for cloning (amplification of the DNA)or for expression. Various vectors are publicly available. The vectormay, for example, be in the form of a plasmid, cosmid, viral particle,or phage. The appropriate nucleic acid sequence may be inserted into thevector by a variety of procedures. In general, DNA is inserted into anappropriate restriction endonuclease site(s) using techniques known inthe art. Vector components generally include, but are not limited to,one or more of a signal sequence, an origin of replication, one or moremarker genes, an enhancer element, a promoter, and a transcriptiontermination sequence. Construction of suitable vectors containing one ormore of these components employs standard ligation techniques which areknown to the skilled artisan.

The PRO may be produced recombinantly not only directly, but also as afusion polypeptide with a heterologous polypeptide, which may be asignal sequence or other polypeptide having a specific cleavage site atthe N-terminus of the mature protein or polypeptide. In general, thesignal sequence may be a component of the vector, or it may be a part ofthe PRO-encoding DNA that is inserted into the vector. The signalsequence may be a prokaryotic signal sequence selected, for example,from the group of the alkaline phosphatase, penicillinase, lpp, orheat-stable enterotoxin II leaders. For yeast secretion the signalsequence may be, e.g., the yeast invertase leader, alpha factor leader(including Saccharomyces and Kluyveromyces α-factor leaders, the latterdescribed in U.S. Pat. No. 5,010,182), or acid phosphatase leader, theC. albicans glucoamylase leader (EP 362,179 published 4 Apr. 1990), orthe signal described in WO 90/13646 published 15 Nov. 1990. In mammaliancell expression, mammalian signal sequences may be used to directsecretion of the protein, such as signal sequences from secretedpolypeptides of the same or related species, as well as viral secretoryleaders.

Both expression and cloning vectors contain a nucleic acid sequence thatenables the vector to replicate in one or more selected host cells. Suchsequences are well known for a variety of bacteria, yeast, and viruses.The origin of replication from the plasmid pBR322 is suitable for mostGram-negative bacteria, the 2μ plasmid origin is suitable for yeast, andvarious viral origins (SV40, polyoma, adenovirus, VSV or BPV) are usefulfor cloning vectors in mammalian cells.

Expression and cloning vectors will typically contain a selection gene,also termed a selectable marker. Typical selection genes encode proteinsthat (a) confer resistance to antibiotics or other toxins, e.g.,ampicillin, neomycin, methotrexate, or tetracycline, (b) complementauxotrophic deficiencies, or (c) supply critical nutrients not availablefrom complex media, e.g., the gene encoding D-alanine racemase forBacilli.

An example of suitable selectable markers for mammalian cells are thosethat enable the identification of cells competent to take up thePRO-encoding nucleic acid, such as DHFR or thymidine kinase. Anappropriate host cell when wild-type DHFR is employed is the CHO cellline deficient in DHFR activity, prepared and propagated as described byUrlaub et al., Proc. Natl. Acad. Sci. USA, 77: 4216 (1980). A suitableselection gene for use in yeast is the trp1 gene present in the yeastplasmid YRp7 [Stinchcomb et al., Nature, 282: 39 (1979); Kingsman etal., Gene, 7: 141 (1979); Tschemper et al., Gene, 10: 157 (1980)]. Thetrp1 gene provides a selection marker for a mutant strain of yeastlacking the ability to grow in tryptophan, for example, ATCC No. 44076or PEP4-1 [Jones, Genetics, 85: 12 (1977)].

Expression and cloning vectors usually contain a promoter operablylinked to the PRO-encoding nucleic acid sequence to direct mRNAsynthesis. Promoters recognized by a variety of potential host cells arewell known. Promoters suitable for use with prokaryotic hosts includethe β-lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281: 544 (1979)], alkalinephosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic AcidsRes., 8: 4057 (1980): EP 36,776], and hybrid promoters such as the tacpromoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80: 21-25 (1983)].Promoters for use in bacterial systems also will contain aShine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO.

Examples of suitable promoting sequences for use with yeast hostsinclude the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J.Biol. Chem., 255: 2073 (1980)] or other glycolytic enzymes [Hess et al.,J. Adv. Enzyme Reg., 7: 149 (1968); Holland, Biochemistry, 17: 4900(1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase,hexokinase, pyruvate decarboxylase, phosphofructokinase,glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvatekinase, triosephosphate isomerase, phosphoglucose isomerase, andglucokinase.

Other yeast promoters, which arc inducible promoters having theadditional advantage of transcription controlled by growth conditions,arc the promoter regions for alcohol dehydrogenase 2, isocytochrome C,acid phosphatase, degradative enzymes associated with nitrogenmetabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase,and enzymes responsible for maltose and galactose utilization. Suitablevectors and promoters for use in yeast expression are further describedin EP 73,657.

PRO transcription from vectors in mammalian host cells is controlled,for example, by promoters obtained from the genomes of viruses such aspolyoma virus, fowlpox virus (UK 2,211,504 published 5 Jul. 1989),adenovirus (such as Adenovirus 2), bovine papilloina virus, aviansarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus andSimian Virus 40 (SV40), from heterologous mammalian promoters, e.g., theactin promoter or an immunoglobulin promoter, and from heat-shockpromoters, provided such promoters are compatible with the host cellsystems.

Transcription of a DNA encoding the PRO by higher eukaryotes may beincreased by inserting an enhancer sequence into the vector. Enhancersare cis-acting elements of DNA, usually about from 10 to 300 bp, thatact on a promoter to increase its transcription. Many enhancer sequencesare now known from mammalian genes (globin, elastase, albumin,α-fetoprotein, and insulin). Typically, however, one will use anenhancer from a eukaryotic cell virus. Examples include the SV40enhancer on the late side of the replication origin (bp 100-270), thecytomegalovirus early promoter enhancer, the polyoma enhancer on thelate side of the replication origin, and adenovirus enhancers. Theenhancer may be spliced into the vector at a position 5′ or 3′ to thePRO coding sequence, but is preferably located at a site 5′ from thepromoter.

Expression vectors used in eukaryotic host cells (yeast, fungi, insect,plant, animal, human, or nucleated cells from other multicellularorganisms) will also contain sequences necessary for the termination oftranscription and for stabilizing the mRNA. Such sequences are commonlyavailable from the 5′ and, occasionally 3′, untranslated regions ofeukaryotic or viral DNAs or cDNAs. These regions contain nucleotidesegments transcribed as polyadenylated fragments in the untranslatedportion of the mRNA encoding PRO.

Still other methods, vectors, and host cells suitable for adaptation tothe synthesis of PRO in recombinant vertebrate cell culture aredescribed in Gething et al., Nature, 293: 620-625 (1981); Mantei et al.,Nature, 281: 40-46 (1979); EP 117,060; and EP 117,058.

4. Detecting Gene Amplification/Expression

Gene amplification and/or expression may be measured in a sampledirectly, for example, by conventional Southern blotting, Northernblotting to quantitate the transcription of mRNA [Thomas, Proc. Natl.Acad. Sci. USA, 77: 5201-5205 (1980)], dot blotting (DNA analysis), orin situ hybridization, using an appropriately labeled probe, based onthe sequences provided herein. Alternatively, antibodies may be employedthat can recognize specific duplexes, including DNA duplexes, RNAduplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. Theantibodies in turn may be labeled and the assay may be carried out wherethe duplex is bound to a surface, so that upon the formation of duplexon the surface, the presence of antibody bound to the duplex can bedetected.

Gene expression, alternatively, may be measured by immunologicalmethods, such as immunohistochemical staining of cells or tissuesections and assay of cell culture or body fluids, to quantitatedirectly the expression of gene product. Antibodies useful forimmunohistochemical staining and/or assay of sample fluids may be eithermonoclonal or polyclonal, and may be prepared in any mammal.Conveniently, the antibodies may be prepared against a native sequencePRO polypeptide or against a synthetic peptide based on the DNAsequences provided herein or against exogenous sequence fused to PRO DNAand encoding a specific antibody epitope.

5. Purification of Polypeptide

Forms of PRO may be recovered from culture medium or from host celllysates. If membrane-bound, it can be released from the membrane using asuitable detergent solution (e.g. Triton-X 100) or by enzymaticcleavage. Cells employed in expression of PRO can be disrupted byvarious physical or chemical means, such as freeze-thaw cycling,sonication, mechanical disruption, or cell lysing agents.

It may be desired to purify PRO from recombinant cell proteins orpolypeptides. The following procedures are exemplary of suitablepurification procedures: by fractionation on an ion-exchange column;ethanol precipitation; reverse phase HPLC; chromatography on silica oron a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE;ammonium sulfate precipitation; gel filtration using, for example,Sephadex G-75; protein A Sepharose columns to remove contaminants suchas IgG; and metal chelating columns to bind epitope-tagged forms of thePRO. Various methods of protein purification may be employed and suchmethods are known in the art and described for example in Deutscher,Methods in Enzymology, 182 (1990); Scopes, Protein Purification:Principles and Practice, Springer-Verlag, New York (1982). Thepurification step(s) selected will depend, for example, on the nature ofthe production process used and the particular PRO produced.

E. Uses for PRO

Nucleotide sequences (or their complement) encoding PRO have variousapplications in the art of molecular biology, including uses ashybridization probes, in chromosome and gene mapping and in thegeneration of anti-sense RNA and DNA. PRO nucleic acid will also beuseful for the preparation of PRO polypeptides by the recombinanttechniques described herein.

The full-length native sequence PRO gene, or portions thereof, may beused as hybridization probes for a cDNA library to isolate thefull-length PRO cDNA or to isolate still other cDNAs (for instance,those encoding naturally-occurring variants of PRO or PRO from otherspecies) which have a desired sequence identity to the native PROsequence disclosed herein. Optionally, the length of the probes will beabout 20 to about 50 bases. The hybridization probes may be derived fromat least partially novel regions of the full length native nucleotidesequence wherein those regions may be determined without undueexperimentation or from genomic sequences including promoters, enhancerelements and introns of native sequence PRO. By way of example, ascreening method will comprise isolating the coding region of the PROgene using the known DNA sequence to synthesize a selected probe ofabout 40 bases. Hybridization probes may be labeled by a variety oflabels, including radionucleotides such as ³²P or ³⁵S, or enzymaticlabels such as alkaline phosphatase coupled to the probe viaavidin/biotin coupling systems. Labeled probes having a sequencecomplementary to that of the PRO gene of the present invention can beused to screen libraries of human cDNA, genomic DNA or mRNA to determinewhich members of such libraries the probe hybridizes to. Hybridizationtechniques are described in further detail in the Examples below.

Any EST sequences disclosed in the present application may similarly beemployed as probes, using the methods disclosed herein.

Other useful fragments of the PRO nucleic acids include antisense orsense oligonucleotides comprising a singe-stranded nucleic acid sequence(either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRODNA (antisense) sequences. Antisense or sense oligonucleotides,according to the present invention, comprise a fragment of the codingregion of PRO DNA. Such a fragment generally comprises at least about 14nucleotides, preferably from about 14 to 30 nucleotides. The ability toderive an antisense or a sense oligonucleotide, based upon a cDNAsequence encoding a given protein is described in, for example, Steinand Cohen (Cancer Res. 48: 2659, 1988) and van der Krol et al.(BioTechniques 6: 958, 1988).

Binding of antisense or sense oligonucleotides to target nucleic acidsequences results in the formation of duplexes that block transcriptionor translation of the target sequence by one of several means, includingenhanced degradation of the duplexes, premature termination oftranscription or translation, or by other means. The antisenseoligonucleotides thus may be used to block expression of PRO proteins.Antisense or sense oligonucleotides further comprise oligonucleotideshaving modified sugar-phosphodiester backbones (or other sugar linkages,such as those described in WO 91/06629) and wherein such sugar linkagesare resistant to endogenous nucleases. Such oligonucleotides withresistant sugar linkages are stable in vivo (i.e., capable of resistingenzymatic degradation) but retain sequence specificity to be able tobind to target nucleotide sequences.

Other examples of sense or antisense oligonucleotides include thoseoligonucleotides which are covalently linked to organic moieties, suchas those described in WO 90/10048, and other moieties that increasesaffinity of the oligonucleotide for a target nucleic acid sequence, suchas poly-(L-lysine). Further still, intercalating agents, such asellipticine, and alkylating agents or metal complexes may be attached tosense or antisense oligonucleotides to modify binding specificities ofthe antisense or sense oligonucleotide for the target nucleotidesequence.

Antisense or sense oligonucleotides may be introduced into a cellcontaining the target nucleic acid sequence by any gene transfer method,including, for example, CaPO₄-mediated DNA transfection,electroporation, or by using gene transfer vectors such as Epstein-Barrvirus. In a preferred procedure, an antisense or sense oligonucleotideis inserted into a suitable retroviral vector. A cell containing thetarget nucleic acid sequence is contacted with the recombinantretroviral vector, either in vivo or ex vivo. Suitable retroviralvectors include, but are not limited to, those derived from the murineretrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the doublecopy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).

Sense or antisense oligonucleotides also may be introduced into a cellcontaining the target nucleotide sequence by formation of a conjugatewith a ligand binding molecule, as described in WO 91/04753. Suitableligand binding molecules include, but are not limited to, cell surfacereceptors, growth factors, other cytokines, or other ligands that bindto cell surface receptors. Preferably, conjugation of the ligand bindingmolecule does not substantially interfere with the ability of the ligandbinding molecule to bind to its corresponding molecule or receptor, orblock entry of the sense or antisense oligonucleotide or its conjugatedversion into the cell.

Alternatively, a sense or an antisense oligonucleotide may be introducedinto a cell containing the target nucleic acid sequence by formation ofan oligonucleotide-lipid complex, as described in WO 90/10448. The senseor antisense oligonucleotide-lipid complex is preferably dissociatedwithin the cell by an endogenous lipase.

Antisense or sense RNA or DNA molecules are generally at least about 5bases in length, about 10 bases in length, about 15 bases in length,about 20 bases in length, about 25 bases in length, about 30 bases inlength, about 35 bases in length, about 40 bases in length, about 45bases in length, about 50 bases in length, about 55 bases in length,about 60 bases in length, about 65 bases in length, about 70 bases inlength, about 75 bases in length, about 80 bases in length, about 85bases in length, about 90 bases in length, about 95 bases in length,about 100 bases in length, or more.

The probes may also be employed in PCR techniques to generate a pool ofsequences for identification of closely related PRO coding sequences.

Nucleotide sequences encoding a PRO can also be used to constructhybridization probes for mapping the gene which encodes that PRO and forthe genetic analysis of individuals with genetic disorders. Thenucleotide sequences provided herein may be mapped to a chromosome andspecific regions of a chromosome using known techniques, such as in situhybridization, linkage analysis against known chromosomal markers, andhybridization screening with libraries.

When the coding sequences for PRO encode a protein which binds toanother protein (example, where the PRO is a receptor), the PRO can beused in assays to identify the other proteins or molecules involved inthe binding interaction. By such methods, inhibitors of thereceptor/ligand binding interaction can be identified. Proteins involvedin such binding interactions can also be used to screen for peptide orsmall molecule inhibitors or agonists of the binding interaction. Also,the receptor PRO can be used to isolate correlative ligand(s). Screeningassays can be designed to find lead compounds that mimic the biologicalactivity of a native PRO or a receptor for PRO. Such screening assayswill include assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates. Small molecules contemplated include syntheticorganic or inorganic compounds. The assays can be performed in a varietyof formats, including protein-protein binding assays, biochemicalscreening assays, immunoassays and cell based assays, which are wellcharacterized in the art.

Nucleic acids which encode PRO or its modified forms can also be used togenerate either transgenic animals or “knock out” animals which, inturn, are useful in the development and screening of therapeuticallyuseful reagents. A transgenic animal (e.g., a mouse or rat) is an animalhaving cells that contain a transgene, which transgene was introducedinto the animal or an ancestor of the animal at a prenatal, e.g., anembryonic stage. A transgene is a DNA which is integrated into thegenome of a cell from which a transgenic animal develops. In oneembodiment, cDNA encoding PRO can be used to clone genomic DNA encodingPRO in accordance with established techniques and the genomic sequencesused to generate transgenic animals that contain cells which express DNAencoding PRO. Methods for generating transgenic animals, particularlyanimals such as mice or rats, have become conventional in the art andare described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009.Typically, particular cells would be targeted for PRO transgeneincorporation with tissue-specific enhancers. Transgenic animals thatinclude a copy of a transgene encoding PRO introduced into the germ lineof the animal at an embryonic stage can be used to examine the effect ofincreased expression of DNA encoding PRO. Such animals can be used astester animals for reagents thought to confer protection from, forexample, pathological conditions associated with its overexpression. Inaccordance with this facet of the invention, an animal is treated withthe reagent and a reduced incidence of the pathological condition,compared to untreated animals bearing the transgene, would indicate apotential therapeutic intervention for the pathological condition.

Alternatively, non-human homologues of PRO can be used to construct aPRO “knock out” animal which has a defective or altered gene encodingPRO as a result of homologous recombination between the endogenous geneencoding PRO and altered genomic DNA encoding PRO introduced into anembryonic stem cell of the animal. For example, cDNA encoding PRO can beused to clone genomic DNA encoding PRO in accordance with establishedtechniques. A portion of the genomic DNA encoding PRO can be deleted orreplaced with another gene, such as a gene encoding a selectable markerwhich can be used to monitor integration. Typically, several kilobasesof unaltered flanking DNA (both at the 5′ and 3′ ends) are included inthe vector [see e.g., Thomas and Capecchi, Cell, 51: 503 (1987) for adescription of homologous recombination vectors]. The vector isintroduced into an embryonic stem cell line (e.g., by electroporation)and cells in which the introduced DNA has homologously recombined withthe endogenous DNA are selected [see e.g., Li et al., Cell, 69: 915(1992)]. The selected cells are then injected into a blastocyst of ananimal (e.g., a mouse or rat) to form aggregation chimeras [see e.g.,Bradley, in Teratocarcinomas and Embryonic Stem Cells: A PracticalApproach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. Achimeric embryo can then be implanted into a suitable pseudopregnantfemale foster animal and the embryo brought to term to create a “knockout” animal. Progeny harboring the homologously recombined DNA in theirgerm cells can be identified by standard techniques and used to breedanimals in which all cells of the animal contain the homologouslyrecombined DNA. Knockout animals can be characterized for instance, fortheir ability to defend against certain pathological conditions and fortheir development of pathological conditions due to absence of the PROpolypeptide.

Nucleic acid encoding the PRO polypeptides may also be used in genetherapy. In gene therapy applications, genes are introduced into cellsin order to achieve in vivo synthesis of a therapeutically effectivegenetic product, for example for replacement of a defective gene. “Genetherapy” includes both conventional gene therapy where a lasting effectis achieved by a single treatment, and the administration of genetherapeutic agents, which involves the one time or repeatedadministration of a therapeutically effective DNA or mRNA. AntisenseRNAs and DNAs can be used as therapeutic agents for blocking theexpression of certain genes in vivo. It has already been shown thatshort antisense oligonucleotides can be imported into cells where theyact as inhibitors, despite their low intracellular concentrations causedby their restricted uptake by the cell membrane. (Zamecnik et al., Proc.Natl. Acad. Sci. USA 83: 4143-4146 [1986]). The oligonucleotides can hemodified to enhance their uptake, e.g. by substituting their negativelycharged phosphodiester groups by uncharged groups.

There are a variety of techniques available for introducing nucleicacids into viable cells. The techniques vary depending upon whether thenucleic acid is transferred into cultured cells in vitro, or in vivo inthe cells of the intended host. Techniques suitable for the transfer ofnucleic acid into mammalian cells in vitro include the use of liposomes,electroporation, microinjection, cell fusion, DEAE-dextran, the calciumphosphate precipitation method, etc. The currently preferred in vivogene transfer techniques include transfection with viral (typicallyretroviral) vectors and viral coat protein-liposome mediatedtransfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]).In some situations it is desirable to provide the nucleic acid sourcewith an agent that targets the target cells, such as an antibodyspecific for a cell surface membrane protein or the target cell, aligand for a receptor on the target cell, etc. Where liposomes areemployed, proteins which bind to a cell surface membrane proteinassociated with endocytosis may be used for targeting and/or tofacilitate uptake, e.g. capsid proteins or fragments thereof tropic fora particular cell type, antibodies for proteins which undergointernalization in cycling, proteins that target intracellularlocalization and enhance intracellular half-life. The technique ofreceptor-mediated endocytosis is described, for example, by Wu et al.,J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl.Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and genetherapy protocols see Anderson et al., Science 256, 808-813 (1992).

The PRO polypeptides described herein may also be employed as molecularweight markers for protein electrophoresis purposes and the isolatednucleic acid sequences may be used for recombinantly expressing thosemarkers.

The nucleic acid molecules encoding the PRO polypeptides or fragmentsthereof described herein are useful for chromosome identification. Inthis regard, there exists an ongoing need to identify new chromosomemarkers, since relatively few chromosome marking reagents, based uponactual sequence data are presently available. Each PRO nucleic acidmolecule of the present invention can be used as a chromosome marker.

The PRO polypeptides and nucleic acid molecules of the present inventionmay also be used for tissue typing, wherein the PRO polypeptides of thepresent invention may be differentially expressed in one tissue ascompared to another. PRO nucleic acid molecules will find use forgenerating probes for PCR, Northern analysis, Southern analysis andWestern analysis.

The PRO polypeptides described herein may also be employed astherapeutic agents. The PRO polypeptides of the present invention can beformulated according to known methods to prepare pharmaceutically usefulcompositions, whereby the PRO product hereof is combined in admixturewith a pharmaceutically acceptable carrier-vehicle. Therapeuticformulations are prepared for storage by mixing the active ingredienthaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof lyophilized formulations or aqueous solutions. Acceptable carriers,excipients or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrateand other organic acids; antioxidants including ascorbic acid; lowmolecular weight (less than about 10 residues) polypeptides; proteins,such as serum albumin, gelatin or immunoglobulins; hydrophilic polymerssuch as polyvinylpyrrolidone, amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides and othercarbohydrates including glucose, mannose, or dextrins; chelating agentssuch as EDTA; sugar alcohols such as mannitol or sorbitol; salt-formingcounterions such as sodium; and/or nonionic surfactants such as TWEEN™,PLURONICS™ or PEG.

The formulations to be used for in vivo administration must be sterile.This is readily accomplished by filtration through sterile filtrationmembranes, prior to or following lyophilization and reconstitution.

Therapeutic compositions herein generally are placed into a containerhaving a sterile access port, for example, an intravenous solution bagor vial having a stopper pierceable by a hypodermic injection needle.

The route of administration is in accord with known methods, e.g.injection or infusion by intravenous, intraperitoneal, intracerebral,intramuscular, intraocular, intraarterial or intralesional routes,topical administration, or by sustained release systems.

Dosages and desired drug concentrations of pharmaceutical compositionsof the present invention may vary depending on the particular useenvisioned. The determination of the appropriate dosage or route ofadministration is well within the skill of an ordinary physician. Animalexperiments provide reliable guidance for the determination of effectivedoses for human therapy. Interspecies scaling of effective doses can beperformed following the principles laid down by Mordenti, J. andChappell, W. “The use of interspecies scaling in toxicokinetics” InToxicokinetics and New Drug Development, Yacobi et al., Eds., PergamonPress, New York 1989, pp. 42-96.

When in vivo administration of a PRO polypeptide or agonist orantagonist thereof is employed, normal dosage amounts may vary fromabout 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day,preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the routeof administration. Guidance as to particular dosages and methods ofdelivery is provided in the literature; see, for example, U.S. Pat. No.4,657,760; 5,206,344; or 5,225,212. It is anticipated that differentformulations will be effective for different treatment compounds anddifferent disorders, that administration targeting one organ or tissue,for example, may necessitate delivery in a manner different from that toanother organ or tissue.

Where sustained-release administration of a PRO polypeptide is desiredin a formulation with release characteristics suitable for the treatmentof any disease or disorder requiring administration of the PROpolypeptide, microencapsulation of the PRO polypeptide is contemplated.Microencapsulation of recombinant proteins for sustained release hasbeen successfully performed with human growth hormone (rhGH),interferon-(rhIFN-), interleukin-2, and MN rgp120. Johnson et al., Nat.Med., 2: 795-799 (1996); Yasuda, Biomed. Ther., 27: 1221-1223 (1993);Hora et al., Bio/Technology, 8: 755-758 (1990); Cleland, “Design andProduction of Single Immunization Vaccines Using PolylactidePolyglycolide Microsphere Systems,” in Vaccine Design: The Subunit andAdjuvant Approach, Powell and Newman, eds, (Plenum Press: New York,1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat.No. 5,654,010.

The sustained-release formulations of these proteins were developedusing poly-lactic-coglycolic acid (PLGA) polymer due to itsbiocompatibility and wide range of biodegradable properties. Thedegradation products of PLGA, lactic and glycolic acids, can be clearedquickly within the human body. Moreover, the degradability of thispolymer can be adjusted from months to years depending on its molecularweight and composition. Lewis, “Controlled release of bioactive agentsfrom lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.),Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: NewYork, 1990), pp. 1-41.

This invention encompasses methods of screening compounds to identifythose that mimic the PRO polypeptide (agonists) or prevent the effect ofthe PRO polypeptide (antagonists). Screening assays for antagonist drugcandidates are designed to identify compounds that bind or complex withthe PRO polypeptides encoded by the genes identified herein, orotherwise interfere with the interaction of the encoded polypeptideswith other cellular proteins. Such screening assays will include assaysamenable to high-throughput screening of chemical libraries, making themparticularly suitable for identifying small molecule drug candidates.

The assays can be performed in a variety of formats, includingprotein-protein binding assays, biochemical screening assays,immunoassays, and cell-based assays, which are well characterized in theart.

All assays for antagonists are common in that they call for contactingthe drug candidate with a PRO polypeptide encoded by a nucleic acididentified herein under conditions and for a time sufficient to allowthese two components to interact.

In binding assays, the interaction is binding and the complex formed canbe isolated or detected in the reaction mixture. In a particularembodiment, the PRO polypeptide encoded by the gene identified herein orthe drug candidate is immobilized on a solid phase, e.g., on amicrotiter plate, by covalent or non-covalent attachments. Non-covalentattachment generally is accomplished by coating the solid surface with asolution of the PRO polypeptide and drying. Alternatively, animmobilized antibody, e.g., a monoclonal antibody, specific for the PROpolypeptide to be immobilized can be used to anchor it to a solidsurface. The assay is performed by adding the non-immobilized component,which may be labeled by a detectable label, to the immobilizedcomponent, e.g., the coated surface containing the anchored component.When the reaction is complete, the non-reacted components are removed,e.g., by washing, and complexes anchored on the solid surface aredetected. When the originally non-immobilized component carries adetectable label, the detection of label immobilized on the surfaceindicates that complexing occurred. Where the originally non-immobilizedcomponent does not carry a label, complexing can be detected, forexample, by using a labeled antibody specifically binding theimmobilized complex.

If the candidate compound interacts with but does not bind to aparticular PRO polypeptide encoded by a gene identified herein, itsinteraction with that polypeptide can be assayed by methods well knownfor detecting protein-protein interactions. Such assays includetraditional approaches, such as, e.g., cross-linking,co-immunoprecipitation, and co-purification through gradients orchromatographic columns. In addition, protein-protein interactions canbe monitored by using a yeast-based genetic system described by Fieldsand co-workers (Fields and Song, Nature (London), 340: 245-246 (1989);Chien et al., Proc. Natl. Acad. Sci. USA, 88: 9578-9582 (1991)) asdisclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA, 89:5789-5793 (1991). Many transcriptional activators, such as yeast GALA,consist of two physically discrete modular domains, one acting as theDNA-binding domain, the other one functioning as thetranscription-activation domain. The yeast expression system describedin the foregoing publications (generally referred to as the “two-hybridsystem”) takes advantage of this property, and employs two hybridproteins, one in which the target protein is fused to the DNA-bindingdomain of GAL4, and another, in which candidate activating proteins arefused to the activation domain. The expression of a GAL1-lacZ reportergene under control of a GAL4-activated promoter depends onreconstitution of GAL4 activity via protein-protein interaction.Colonies containing interacting polypeptides are detected with achromogenic substrate for β-galactosidase. A complete kit (MATCHMAKER™)for identifying protein-protein interactions between two specificproteins using the two-hybrid technique is commercially available fromClontech. This system can also be extended to map protein domainsinvolved in specific protein interactions as well as to pinpoint aminoacid residues that are crucial for these interactions.

Compounds that interfere with the interaction of a gene encoding a PROpolypeptide identified herein and other intra- or extracellularcomponents can be tested as follows: usually a reaction mixture isprepared containing the product of the gene and the intra- orextracellular component under conditions and for a time allowing for theinteraction and binding of the two products. To test the ability of acandidate compound to inhibit binding, the reaction is run in theabsence and in the presence of the test compound. In addition, a placebomay be added to a third reaction mixture, to serve as positive control.The binding (complex formation) between the test compound and the intra-or extracellular component present in the mixture is monitored asdescribed hereinabove. The formation of a complex in the controlreaction(s) but not in the reaction mixture containing the test compoundindicates that the test compound interferes with the interaction of thetest compound and its reaction partner.

To assay for antagonists, the PRO polypeptide may be added to a cellalong with the compound to be screened for a particular activity and theability of the compound to inhibit the activity of interest in thepresence of the PRO polypeptide indicates that the compound is anantagonist to the PRO polypeptide. Alternatively, antagonists may bedetected by combining the PRO polypeptide and a potential antagonistwith membrane-bound PRO polypeptide receptors or recombinant receptorsunder appropriate conditions for a competitive inhibition assay. The PROpolypeptide can be labeled, such as by radioactivity, such that thenumber of PRO polypeptide molecules bound to the receptor can be used todetermine the effectiveness of the potential antagonist. The geneencoding the receptor can be identified by numerous methods known tothose of skill in the art, for example, ligand panning and FACS sorting.Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).Preferably, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the PRO polypeptide and a cDNAlibrary created from this RNA is divided into pools and used totransfect COS cells or other cells that are not responsive to the PROpolypeptide. Transfected cells that are grown on glass slides areexposed to labeled PRO polypeptide. The PRO polypeptide can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase. Following fixation andincubation, the slides are subjected to autoradiographic analysis.Positive pools are identified and sub-pools are prepared andre-transfected using an interactive sub-pooling and re-screeningprocess, eventually yielding a single clone that encodes the putativereceptor.

As an alternative approach for receptor identification, labeled PROpolypeptide can be photoaffinity-linked with cell membrane or extractpreparations that express the receptor molecule. Cross-linked materialis resolved by PAGE and exposed to X-ray film. The labeled complexcontaining the receptor can be excised, resolved into peptide fragments,and subjected to protein micro-sequencing. The amino acid sequenceobtained from micro-sequencing would be used to design a set ofdegenerate oligonucleotide probes to screen a cDNA library to identifythe gene encoding the putative receptor.

In another assay for antagonists, mammalian cells or a membranepreparation expressing the receptor would be incubated with labeled PROpolypeptide in the presence of the candidate compound. The ability ofthe compound to enhance or block this interaction could then bemeasured.

More specific examples of potential antagonists include anoligonucleotide that binds to the fusions of immunoglobulin with PROpolypeptide, and, in particular, antibodies including, withoutlimitation, poly- and monoclonal antibodies and antibody fragments,single-chain antibodies, anti-idiotypic antibodies, and chimeric orhumanized versions of such antibodies or fragments, as well as humanantibodies and antibody fragments. Alternatively, a potential antagonistmay be a closely related protein, for example, a mutated form of the PROpolypeptide that recognizes the receptor but imparts no effect, therebycompetitively inhibiting the action of the PRO polypeptide.

Another potential PRO polypeptide antagonist is an antisense RNA or DNAconstruct prepared using antisense technology, where, e.g., an antisenseRNA or DNA molecule acts to block directly the translation of mRNA byhybridizing to targeted mRNA and preventing protein translation.Antisense technology can be used to control gene expression throughtriple-helix formation or antisense DNA or RNA, both of which methodsare based on binding of a polynucleotide to DNA or RNA. For example, the5′ coding portion of the polynucleotide sequence, which encodes themature PRO polypeptides herein, is used to design an antisense RNAoligonucleotide of from about 10 to 40 base pairs in length. A DNAoligonucleotide is designed to be complementary to a region of the geneinvolved in transcription (triple helix—see Lee et al., Nucl. AcidsRes., 6: 3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan etal., Science, 251: 1360 (1991)), thereby preventing transcription andthe production of the PRO polypeptide. The antisense RNA oligonucleotidehybridizes to the mRNA in vivo and blocks translation of the mRNAmolecule into the PRO polypeptide (antisense—Okano, Neurochem., 56: 560(1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression(CRC Press: Boca Raton, Fla., 1988). The oligonucleotides describedabove can also be delivered to cells such that the antisense RNA or DNAmay be expressed in vivo to inhibit production of the PRO polypeptide.When antisense DNA is used, oligodeoxyribonucleotides derived from thetranslation-initiation site, e.g., between about −10 and +10 positionsof the target gene nucleotide sequence, are preferred.

Potential antagonists include small molecules that bind to the activesite, the receptor binding site, or growth factor or other relevantbinding site of the PRO polypeptide, thereby blocking the normalbiological activity of the PRO polypeptide. Examples of small moleculesinclude, but are not limited to, small peptides or peptide-likemolecules, preferably soluble peptides, and synthetic non-peptidylorganic or inorganic compounds.

Ribozymes are enzymatic RNA molecules capable of catalyzing the specificcleavage of RNA. Ribozymes act by sequence-specific hybridization to thecomplementary target RNA, followed by endonucleolytic cleavage. Specificribozyme cleavage sites within a potential RNA target can be identifiedby known techniques. For further details see, e.g., Rossi, CurrentBiology, 4: 469-471 (1994), and PCT publication No. WO 97/33551(published Sep. 18, 1997).

Nucleic acid molecules in triple-helix formation used to inhibittranscription should be single-stranded and composed ofdeoxynucleotides. The base composition of these oligonucleotides isdesigned such that it promotes triple-helix formation via Hoogsteenbase-pairing rules, which generally require sizeable stretches ofpurines or pyrimidines on one strand of a duplex. For further detailssee, e.g., PCT publication No. WO 97/33551, supra.

These small molecules can be identified by any one or more of thescreening assays discussed hereinabove and/or by any other screeningtechniques well known for those skilled in the art.

Uses of the herein disclosed molecules may also be based upon thepositive functional assay hits disclosed and described below.

F. Anti-PRO Antibodies

The present invention further provides anti-PRO antibodies. Exemplaryantibodies include polyclonal, monoclonal, humanized, bispecific, andheteroconjugate antibodies.

1. Polyclonal Antibodies

The anti-PRO antibodies may comprise polyclonal antibodies. Methods ofpreparing polyclonal antibodies are known to the skilled artisan.Polyclonal antibodies can be raised in a mammal, for example, by one ormore injections of an immunizing agent and, if desired, an adjuvant.Typically, the immunizing agent and/or adjuvant will be injected in themammal by multiple subcutaneous or intraperitoneal injections. Theimmunizing agent may include the PRO polypeptide or a fusion proteinthereof. It may be useful to conjugate the immunizing agent to a proteinknown to be immunogenic in the mammal being immunized. Examples of suchimmunogenic proteins include but are not limited to keyhole limpethemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsininhibitor. Examples of adjuvants which may be employed include Freund'scomplete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A,synthetic trehalose dicorynomycolate). The immunization protocol may beselected by one skilled in the art without undue experimentation.

2. Monoclonal Antibodies

The anti-PRO antibodies may, alternatively, be monoclonal antibodies.Monoclonal antibodies may be prepared using hybridoma methods, such asthose described by Kohler and Milstein, Nature, 256: 495 (1975). In ahybridoma method, a mouse, hamster, or other appropriate host animal, istypically immunized with an immunizing agent to elicit lymphocytes thatproduce or are capable of producing antibodies that will specificallybind to the immunizing agent. Alternatively, the lymphocytes may beimmunized in vitro.

The immunizing agent will typically include the PRO polypeptide or afusion protein thereof. Generally, either peripheral blood lymphocytes(“PBLs”) are used if cells of human origin are desired, or spleen cellsor lymph node cells are used if non-human mammalian sources are desired.The lymphocytes are then fused with an immortalized cell line using asuitable fusing agent, such as polyethylene glycol, to form a hybridomacell [Goding, Monoclonal Antibodies: Principles and Practice, AcademicPress, (1986) pp. 59-103]. Immortalized cell lines are usuallytransformed mammalian cells, particularly myeloma cells of rodent,bovine and human origin. Usually, rat or mouse myeloma cell lines areemployed. The hybridoma cells may be cultured in a suitable culturemedium that preferably contains one or more substances that inhibit thegrowth or survival of the unfused, immortalized cells. For example, ifthe parental cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the hybridomastypically will include hypoxanthine, aminopterin, and thymidine (“HATmedium”), which substances prevent the growth of HGPRT-deficient cells.

Preferred immortalized cell lines are those that fuse efficiently,support stable high level expression of antibody by the selectedantibody-producing cells, and are sensitive to a medium such as HATmedium. More preferred immortalized cell lines are murine myeloma lines,which can be obtained, for instance, from the Salk Institute CellDistribution Center, San Diego, Calif. and the American Type CultureCollection, Manassas, Va. Human myeloma and mouse-human heteromyelomacell lines also have been described for the production of humanmonoclonal antibodies [Kozbor, J. Immunol. 33: 3001 (1984); Brodeur etal. Monoclonal Antibody Production Techniques and Applications, MarcelDekker, Inc., New York, (1987) pp. 51-63].

The culture medium in which the hybridoma cells are cultured can then beassayed for the presence of monoclonal antibodies directed against PRO.Preferably, the binding specificity of monoclonal antibodies produced bythe hybridoma cells is determined by immunoprecipitation or by an invitro binding assay, such as radioimmunoassay (RIA) or enzyme-linkedimmunoabsorbent assay (ELISA). Such techniques and assays are known inthe art. The binding affinity of the monoclonal antibody can, forexample, be determined by the Scatchard analysis of Munson and Pollard,Anal. Biochem., 107: 220 (1980).

After the desired hybridoma cells are identified, the clones may besubcloned by limiting dilution procedures and grown by standard methods[Goding, supra]. Suitable culture media for this purpose include, forexample, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium.Alternatively, the hybridoma cells may be grown in vivo as ascites in amammal.

The monoclonal antibodies secreted by the subclones may be isolated orpurified from the culture medium or ascites fluid by conventionalimmunoglobulin purification procedures such as, for example, proteinA-Sepharose, hydroxylapatite chromatography, gel electrophoresis,dialysis, or affinity chromatography.

The monoclonal antibodies may also be made by recombinant DNA methods,such as those described in U.S. Pat. No. 4,816,567. DNA encoding themonoclonal antibodies of the invention can be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of murine antibodies). The hybridoma cells of theinvention serve as a preferred source of such DNA. Once isolated, theDNA may be placed into expression vectors, which are then transfectedinto host cells such as simian COS cells, Chinese hamster ovary (CHO)cells, or myeloma cells that do not otherwise produce immunoglobulinprotein, to obtain the synthesis of monoclonal antibodies in therecombinant host cells. The DNA also may be modified, for example, bysubstituting the coding sequence for human heavy and light chainconstant domains in place of the homologous murine sequences [U.S. Pat.No. 4,816,567; Morrison et al., supral or by covalently joining to theimmunoglobulin coding sequence all or part of the coding sequence for anon-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptidecan be substituted for the constant domains of an antibody of theinvention, or can be substituted for the variable domains of oneantigen-combining site of an antibody of the invention to create achimeric bivalent antibody.

The antibodies may be monovalent antibodies. Methods for preparingmonovalent antibodies are well known in the art. For example, one methodinvolves recombinant expression of immunoglobulin light chain andmodified heavy chain. The heavy chain is truncated generally at anypoint in the Fc region so as to prevent heavy chain crosslinking.Alternatively, the relevant cysteine residues are substituted withanother amino acid residue or are deleted so as to prevent crosslinking.

In vitro methods are also suitable for preparing monovalent antibodies.Digestion of antibodies to produce fragments thereof, particularly, Fabfragments, can be accomplished using routine techniques known in theart.

3. Human and Humanized Antibodies

The anti-PRO antibodies of the invention may further comprise humanizedantibodies or human antibodies. Humanized forms of non-human (e.g.,murine) antibodies are chimeric immunoglobulins, immunoglobulin chainsor fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or otherantigen-binding subsequences of antibodies) which contain minimalsequence derived from non-human immunoglobulin. Humanized antibodiesinclude human immunoglobulins (recipient antibody) in which residuesfrom a complementary determining region (CDR) of the recipient arereplaced by residues from a CDR of a non-human species (donor antibody)such as mouse, rat or rabbit having the desired specificity, affinityand capacity. In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fe), typically that of a humanimmunoglobulin [Jones et al., Nature, 321: 522-525 (1986); Riechmann etal., Nature, 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol.,2: 593-596 (1992)].

Methods for humanizing non-human antibodies are well known in the art.Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed following the method of Winter and co-workers[Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature,332: 323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)],by substituting rodent CDRs or CDR sequences for the correspondingsequences of a human antibody. Accordingly, such “humanized” antibodiesare chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantiallyless than an intact human variable domain has been substituted by thecorresponding sequence from a non-human species. In practice, humanizedantibodies are typically human antibodies in which some CDR residues andpossibly some FR residues are substituted by residues from analogoussites in rodent antibodies.

Human antibodies can also be produced using various techniques known inthe art, including phage display libraries [Hoogenboom and Winter, J.Mol. Biol., 227: 381 (1991); Marks et al., J. Mol. Biol. 222: 581(1991)]. The techniques of Cole et al. and Boerner et al. are alsoavailable for the preparation of human monoclonal antibodies (Cole etal., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77(1985) and Boerner et al., J. Immunol., 147(1): 86-95 (1991)].Similarly, human antibodies can be made by introducing of humanimmunoglobulin loci into transgenic animals, e.g., mice in which theendogenous immunoglobulin genes have been partially or completelyinactivated. Upon challenge, human antibody production is observed,which closely resembles that seen in humans in all respects, includinggene rearrangement, assembly, and antibody repertoire. This approach isdescribed, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the followingscientific publications: Marks et al., Bio/Technology 10, 779-783(1992); Lonberg et al. Nature 368 856-859 (1994); Morrison, Nature 368,812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996);Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar,Intern. Rev. Immunol. 13 65-93 (1995).

4. Bispecific Antibodies

Bispecific antibodies are monoclonal, preferably human or humanized,antibodies that have binding specificities for at least two differentantigens. In the present case, one of the binding specificities is forthe PRO, the other one is for any other antigen, and preferably for acell-surface protein or receptor or receptor subunit.

Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy-chain/light-chainpairs, where the two heavy chains have different specificities [Milsteinand Cuello, Nature, 305: 537-539 (1983)]. Because of the randomassortment of immunoglobulin heavy and light chains, these hybridomas(quadromas) produce a potential mixture of ten different antibodymolecules, of which only one has the correct bispecific structure. Thepurification of the correct molecule is usually accomplished by affinitychromatography steps. Similar procedures are disclosed in WO 93/08829,published 13 May 1993, and in Traunecker et al., EMBO J., 10: 3655-3659(1991).

Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at least part ofthe hinge, CH2, and CH3 regions. It is preferred to have the firstheavy-chain constant region (CH1) containing the site necessary forlight-chain binding present in at least one of the fusions. DNAsencoding the immunoglobulin heavy-chain fusions and, if desired, theimmunoglobulin light chain, are inserted into separate expressionvectors, and are co-transfected into a suitable host organism. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzmmology, 121: 210 (1986).

According to another approach described in WO 96/27011, the interfacebetween a pair of antibody molecules can be engineered to maximize thepercentage of heterodimers which are recovered from recombinant cellculture. The preferred interface comprises at least a part of the CH3region of an antibody constant domain. In this method, one or more smallamino acid side chains from the interface of the first antibody moleculeare replaced with larger side chains (e.g. tyrosine or tryptophan).Compensatory “cavities” of identical or similar size to the large sidechain(s) are created on the interface of the second antibody molecule byreplacing large amino acid side chains with smaller ones (e.g. alanineor threonine). This provides a mechanism for increasing the yield of theheterodimer over other unwanted end-products such as homodimers.

Bispecific antibodies can be prepared as full length antibodies orantibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniques forgenerating bispecific antibodies from antibody fragments have beendescribed in the literature. For example, bispecific antibodies can beprepared can be prepared using chemical linkage. Brennan et al., Science229: 81 (1985) describe a procedure wherein intact antibodies areproteolytically cleaved to generate F(ab′)₂ fragments. These fragmentsare reduced in the presence of the dithiol complexing agent sodiumarsenite to stabilize vicinal dithiols and prevent intermoleculardisulfide formation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

Fab′ fragments may be directly recovered from E. coli and chemicallycoupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecificantibody F(ab′)₂ molecule. Each Fab′ fragment was separately secretedfrom E. coli and subjected to directed chemical coupling in vitro toform the bispecific antibody. The bispecific antibody thus formed wasable to bind to cells overexpressing the ErbB2 receptor and normal humanT cells, as well as trigger the lytic activity of human cytotoxiclymphocytes against human breast tumor targets.

Various technique for making and isolating bispecific antibody fragmentsdirectly from recombinant cell culture have also been described. Forexample, bispecific antibodies have been produced using leucine zippers.Kostelny et al., J. Immunol. 148(5): 1547-1553 (1992). The leucinezipper peptides from the Fos and Jun proteins were linked to the Fab′portions of two different antibodies by gene fusion. The antibodyhomodimers were reduced at the hinge region to form monomers and thenre-oxidized to form the antibody heterodimers. This method can also beutilized for the production of antibody homodimers. The “diabody”technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for makingbispecific antibody fragments. The fragments comprise a heavy-chainvariable domain (V_(H)) connected to a light-chain variable domain(V_(L)) by a linker which is too short to allow pairing between the twodomains on the same chain. Accordingly, the V_(H) and V_(L) domains ofone fragment are forced to pair with the complementary V_(L) and V_(H)domains of another fragment, thereby forming two antigen-binding sites.Another strategy for making bispecific antibody fragments by the use ofsingle-chain Fv (sFv) dimers has also been reported. See, Gruber et al.,J. Immunol. 152: 5368 (1994).

Antibodies with more than two valencies are contemplated. For example,trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147: 60(1991).

Exemplary bispecific antibodies may bind to two different epitopes on agiven PRO polypeptide herein. Alternatively, an anti-PRO polypeptide armmay be combined with an arm which binds to a triggering molecule on aleukocyte such as a T-cell receptor molecule (e.g. CD2. CD3, CD28, orB7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32)and FcγRIII (CD16) so as to focus cellular defense mechanisms to thecell expressing the particular PRO polypeptide. Bispecific antibodiesmay also be used to localize cytotoxic agents to cells which express aparticular PRO polypeptide. These antibodies possess a PRO-binding armand an arm which binds a cytotoxic agent or a radionuclide chelator,such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody ofinterest binds the PRO polypeptide and further binds tissue factor (TF).

5. Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the presentinvention. Heteroconjugate antibodies are composed of two covalentlyjoined antibodies. Such antibodies have, for example, been proposed totarget immune system cells to unwanted cells [U.S. Pat. No. 4,676,980],and for treatment of HIV infection [WO 91/00360; WO 92/200373; EP03089]. It is contemplated that the antibodies may be prepared in vitrousing known methods in synthetic protein chemistry, including thoseinvolving crosslinking agents. For example, immunotoxins may beconstructed using a disulfide exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, forexample, in U.S. Pat. No. 4,676,980.

6. Effector Function Engineering

It may be desirable to modify the antibody of the invention with respectto effector function, so as to enhance, e.g., the effectiveness of theantibody in treating cancer. For example, cysteine residue(s) may beintroduced into the Fc region, thereby allowing interchain disulfidebond formation in this region. The homodimeric antibody thus generatedmay have improved internalization capability and/or increasedcomplement-mediated cell killing and antibody-dependent cellularcytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195(1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimericantibodies with enhanced anti-tumor activity may also be prepared usingheterobifunctional cross-linkers as described in Wolff et al. CancerResearch, 53: 2560-2565 (1993). Alternatively, an antibody can beengineered that has dual Fc regions and may thereby have enhancedcomplement lysis and ADCC capabilities. See Stevenson et al.,Anti-Cancer Drug Design, 3: 219-230 (1989).

7. Immunoconjugates

The invention also pertains to immunoconjugates comprising an antibodyconjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin(e.g., an enzymatically active toxin of bacterial, fungal, plant, oranimal origin, or fragments thereof), or a radioactive isotope (i.e., aradioconjugate).

Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y,and ¹⁸⁶Re. Conjugates of the antibody and cytotoxic agent are made usinga variety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such asbis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026.

In another embodiment, the antibody may be conjugated to a “receptor”(such streptavidin) for utilization in tumor pretargeting wherein theantibody-receptor conjugate is administered to the patient, followed byremoval of unbound conjugate from the circulation using a clearing agentand then administration of a “ligand” (e.g., avidin) that is conjugatedto a cytotoxic agent (e.g., a radionucleotide).

8. Immunoliposomes

The antibodies disclosed herein may also be formulated asimmunoliposomes. Liposomes containing the antibody are prepared bymethods known in the art, such as described in Epstein et al., Proc.Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl. Acad.Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556.

Particularly useful liposomes can he generated by the reverse-phaseevaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of the antibody of the present invention can beconjugated to the liposomes as described in Martin et al., J. Biol.Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. Achemotherapeutic agent (such as Doxorubicin) is optionally containedwithin the liposome. See Gabizon et al., J. National Cancer Inst.,81(19): 1484 (1989).

9. Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a PRO polypeptide identified herein, aswell as other molecules identified by the screening assays disclosedhereinbefore, can be administered for the treatment of various disordersin the form of pharmaceutical compositions.

If the PRO polypeptide is intracellular and whole antibodies are used asinhibitors, internalizing antibodies are preferred. However,lipofections or liposomes can also be used to deliver the antibody, oran antibody fragment, into cells. Where antibody fragments are used, thesmallest inhibitory fragment that specifically binds to the bindingdomain of the target protein is preferred. For example, based upon thevariable-region sequences of an antibody, peptide molecules can bedesigned that retain the ability to bind the target protein sequence.Such peptides can be synthesized chemically and/or produced byrecombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad.Sci. USA, 90: 7889-7893 (1993). The formulation herein may also containmore than one active compound as necessary for the particular indicationbeing treated, preferably those with complementary activities that donot adversely affect each other. Alternatively, or in addition, thecomposition may comprise an agent that enhances its function, such as,for example, a cytotoxic agent, cytokine, chemotherapeutic agent, orgrowth-inhibitory agent. Such molecules are suitably present incombination in amounts that are effective for the purpose intended.

The active ingredients may also be entrapped in microcapsules prepared,for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles, andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences, supra.

The formulations to be used for in vivo administration must be sterile.This is readily accomplished by filtration through sterile filtrationmembranes.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody, which matrices are in theform of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. Whilepolymers such as ethylene-vinyl acetate and lactic acid-glycolic acidenable release of molecules for over 100 days, certain hydrogels releaseproteins for shorter time periods. When encapsulated antibodies remainin the body for a long time, they may denature or aggregate as a resultof exposure to moisture at 37° C., resulting in a loss of biologicalactivity and possible changes in immunogenicity. Rational strategies canbe devised for stabilization depending on the mechanism involved. Forexample, if the aggregation mechanism is discovered to be intermolecularS—S bond formation through thio-disulfide interchange, stabilization maybe achieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

G. Uses for anti-PRO Antibodies

The anti-PRO antibodies of the invention have various utilities. Forexample, anti-PRO antibodies may be used in diagnostic assays for PRO,e.g., detecting its expression in specific cells, tissues, or serum.Various diagnostic assay techniques known in the art may be used, suchas competitive binding assays, direct or indirect sandwich assays andimmunoprecipitation assays conducted in either heterogeneous orhomogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques,CRC Press, Inc. (1987) pp. 147-158]. The antibodies used in thediagnostic assays can be labeled with a detectable moiety. Thedetectable moiety should be capable of producing, either directly orindirectly, a detectable signal. For example, the detectable moiety maybe a radioisotope, such as ³H, ₁₄C, ³²P, ³⁵S, or ¹²⁵I, a fluorescent orchemiluminescent compound, such as fluorescein isothiocyanate,rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase,beta-galactosidase or horseradish peroxidase. Any method known in theart for conjugating the antibody to the detectable moiety may beemployed, including those methods described by Hunter et al., Nature,144: 945 (1962); David et al., Biochemistry, 13: 1014 (1974); Pain etal., J. Immunol. Meth., 40: 219 (1981); and Nygren, J. Histochem, andCytochem., 30: 407 (1982).

Anti-PRO antibodies also are useful for the affinity purification of PROfrom recombinant cell culture or natural sources. In this process, theantibodies against PRO are immobilized on a suitable support, such aSephadex resin or filter paper, using methods well known in the art. Theimmobilized antibody then is contacted with a sample containing the PROto be purified, and thereafter the support is washed with a suitablesolvent that will remove substantially all the material in the sampleexcept the PRO, which is bound to the immobilized antibody. Finally, thesupport is washed with another suitable solvent that will release thePRO from the antibody.

The following examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

All patent and literature references cited in the present specificationare hereby incorporated by reference in their entirety.

EXAMPLES

Commercially available reagents referred to in the examples were usedaccording to manufacturer's instructions unless otherwise indicated. Thesource of those cells identified in the following examples, andthroughout the specification, by ATCC accession numbers is the AmericanType Culture Collection, Manassas, Va.

Example 1 Extracellular Domain Homology Screening to Identify NovelPolypeptides and cDNA Encoding Therefor

The extracellular domain (ECD) sequences (including the secretion signalsequence, if any) from about 950 known secreted proteins from theSwiss-Prot public database were used to search EST databases. The ESTdatabases included public databases (e.g., Dayhoff, GenBank), andproprietary databases (e.g. LIFESEQ™, Incyte Pharmaceuticals, Palo Alto,Calif.). The search was performed using the computer program BLAST orBLAST-2 (Altschul et al., Methods in Enzymology 266: 460-480 (1996)) asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Those comparisons with a BLAST score of 70 (or insome cases 90) or greater that did not encode known proteins wereclustered and assembled into consensus DNA sequences with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.).

Using this extracellular domain homology screen, consensus DNA sequenceswere assembled relative to the other identified EST sequences usingphrap. In addition, the consensus DNA sequences obtained were often (butnot always) extended using repeated cycles of BLAST or BLAST-2 and phrapto extend the consensus sequence as far as possible using the sources ofEST sequences discussed above.

Based upon the consensus sequences obtained as described above,oligonucleotides were then synthesized and used to identify by PCR acDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for a PROpolypeptide. Forward and reverse PCR primers generally range from 20 to30 nucleotides and are often designed to give a PCR product of about100-1000 bp in length. The probe sequences are typically 40-55 bp inlength. In some cases, additional oligonucleotides are synthesized whenthe consensus sequence is greater than about 1-1.5 kbp. In order toscreen several libraries for a full-length clone, DNA from the librarieswas screened by PCR amplification, as per Ausubel et al., CurrentProtocols in Molecular Biology, with the PCR primer pair. A positivelibrary was then used to isolate clones encoding the gene of interestusing the probe oligonucleotide and one of the primer pairs.

The cDNA libraries used to isolate the cDNA clones were constructed bystandard methods using commercially available reagents such as thosefrom Invitrogen, San Diego, Calif. The cDNA was primed with oligo dTcontaining a NotI site, linked with blunt to SalI hemikinased adaptors,cleaved with NotI, sized appropriately by gel electrophoresis, andcloned in a defined orientation into a suitable cloning vector (such aspRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain theSfiI site; see, Holmes et al., Science, 253: 1278-1280 (1991)) in theunique XhoI and NotI sites.

Example 2 Isolation of cDNA Clones by Amylase Screening

1. Preparation of Oligo dT Primed cDNA Library

mRNA was isolated from a human tissue of interest using reagents andprotocols from Invitrogen, San Diego, Calif. (Fast Track 2). This RNAwas used to generate an oligo dT primed cDNA library in the vector pRKSDusing reagents and protocols from Life Technologies, Gaithersburg, Md.(Super Script Plasmid System). In this procedure, the double strandedcDNA was sized to greater than 1000 bp and the SalI/NotI tinkered cDNAwas cloned into XhoI/NotI cleaved vector. pRK5D is a cloning vector thathas an sp6 transcription initiation site followed by an SfiI restrictionenzyme site preceding the XhoI/NotI cDNA cloning sites.

2. Preparation of Random Primed cDNA Library

A secondary cDNA library was generated in order to preferentiallyrepresent the 5′ ends of the primary cDNA clones. Sp6 RNA was generatedfrom the primary library (described above), and this RNA was used togenerate a random primed cDNA library in the vector pSST-AMY.0 usingreagents and protocols from Life Technologies (Super Script PlasmidSystem, referenced above). In this procedure the double stranded cDNAwas sized to 500-1000 bp, tinkered with blunt to NotI adaptors, cleavedwith SfiI, and cloned into SfiI/NotI cleaved vector. pSST-AMY.0 is acloning vector that has a yeast alcohol dehydrogenase promoter precedingthe cDNA cloning sites and the mouse amylase sequence (the maturesequence without the secretion signal) followed by the yeast alcoholdehydrogenase terminator, after the cloning sites. Thus, cDNAs clonedinto this vector that are fused in frame with amylase sequence will leadto the secretion of amylase from appropriately transfected yeastcolonies.

3. Transformation and Detection

DNA from the library described in paragraph 2 above was chilled on iceto which was added electrocompetent DH10B bacteria (Life Technologies,20 ml). The bacteria and vector mixture was then electroporated asrecommended by the manufacturer. Subsequently, SOC media (LifeTechnologies, 1 ml) was added and the mixture was incubated at 37° C.for 30 minutes. The transformants were then plated onto 20 standard 150mm LB plates containing ampicillin and incubated for 16 hours (37° C.).Positive colonies were scraped off the plates and the DNA was isolatedfrom the bacterial pellet using standard protocols, e.g. CsCl-gradient.The purified DNA was then carried on to the yeast protocols below.

The yeast methods were divided into three categories: (1) Transformationof yeast with the plasmid/cDNA combined vector; (2) Detection andisolation of yeast clones secreting amylase; and (3) PCR amplificationof the insert directly from the yeast colony and purification of the DNAfor sequencing and further analysis.

The yeast strain used was HD56-5A (ATCC-90785). This strain has thefollowing genotype: MAT alpha, ura3-52, leu2-3, leu2-112, his3-11,his3-15, MAL⁺, SUC⁺, GAL⁺. Preferably, yeast mutants can be employedthat have deficient post-translational pathways. Such mutants may havetranslocation deficient alleles in sec71, sec72, sec62, with truncatedsec71 being most preferred. Alternatively, antagonists (includingantisense nucleotides and/or ligands) which interfere with the normaloperation of these genes, other proteins implicated in this posttranslation pathway (e.g., SEC61p, SEC72p, SEC62p, SEC63p, TDJ1porSSA1p-4p) or the complex formation of these proteins may also bepreferably employed in combination with the amylase-expressing yeast.

Transformation was performed based on the protocol outlined by Gietz etal., Nucl. Acid. Res., 20: 1425 (1992). Transformed cells were theninoculated from agar into YEPD complex media broth (100 ml) and grownovernight at 30° C. The YEPD broth was prepared as described in Kaiseret al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold SpringHarbor, N.Y., p. 207 (1994). The overnight culture was then diluted toabout 2×10⁶ cells/ml (approx. OD₆₀₀=0.1) into fresh YEPD broth (500 ml)and regrown to 1×10⁷ cells/ml (approx. OD₆₀₀=0.4−0.5).

The cells were then harvested and prepared for transformation bytransfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5minutes, the supernatant discarded, and then resuspended into sterilewater, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in aBeckman GS-6KR centrifuge. The supernatant was discarded and the cellswere subsequently washed with LiAc/TE (10 ml, 10 mM Tris-HCl, 1 mM EDTApH 7.5, 100 mM Li₂OOCCH₃), and resuspended into LiAc/TE (2.5 ml).

Transformation took place by mixing the prepared cells (100 μl) withfreshly denatured single stranded salmon testes DNA (Lofstrand Labs,Gaithersburg, Md.) and transforming DNA (1 μg, vol. <10 μl) in microfugetubes. The mixture was mixed briefly by vortexing, then 40% PEG/TE (600μl, 40% polyethylene glycol-4000, 10 mM Tris-HCl, 1 mM EDTA, 100 mMLi₂OOCCH₃, pH 7.5) was added. This mixture was gently mixed andincubated at 30° C. while agitating for 30 minutes. The cells were thenheat shocked at 42° C. for 15 minutes, and the reaction vesselcentrifuged in a microfuge at 12,000 rpm for 5-10 seconds, decanted andresuspended into TE (500 μl, 10 mM Tris-HCl, 1 mM EDTA pH 7.5) followedby recentrifugation. The cells were then diluted into TE (1 ml) andaliquots (200 μl) were spread onto the selective media previouslyprepared in 150 mm growth plates (VWR).

Alternatively, instead of multiple small reactions, the transformationwas performed using a single, large scale reaction, wherein reagentamounts were scaled up accordingly.

The selective media used was a synthetic complete dextrose agar lackinguracil (SCD-Ura) prepared as described in Kaiser et al., Methods inYeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., p.208-210 (1994). Transformants were grown at 30° C. for 2-3 days.

The detection of colonies secreting amylase was performed by includingred starch in the selective growth media. Starch was coupled to the reddye (Reactive Red-120, Sigma) as per the procedure described by Biely etal., Anal. Biochem., 172: 176-179 (1988). The coupled starch wasincorporated into the SCD-Ura agar plates at a final concentration of0.15% (w/v), and was buffered with potassium phosphate to a pH of 7.0(50-100 mM final concentration).

The positive colonies were picked and streaked across fresh selectivemedia (onto 150 mm plates) in order to obtain well isolated andidentifiable single colonies. Well isolated single colonies positive foramylase secretion were detected by direct incorporation of red starchinto buffered SCD-Ura agar. Positive colonies were determined by theirability to break down starch resulting in a clear halo around thepositive colony visualized directly.

4. Isolation of DNA by PCR Amplification

When a positive colony was isolated, a portion of it was picked by atoothpick and diluted into sterile water (30 μl) in a 96 well plate. Atthis time, the positive colonies were either frozen and stored forsubsequent analysis or immediately amplified. An aliquot of cells (5 μl)was used as a template for the PCR reaction in a 25 μl volumecontaining: 0.5 μl Klentaq (Clontech, Palo Alto, Calif.); 4.0 μl 10 mMdNTP's (Perkin Elmer-Cetus); 2.5 μl Kentaq buffer (Clontech); 0.25 μlforward oligo 1; 0.25 μl reverse oligo 2; 12.5 μl distilled water. Thesequence of the forward oligonucleotide 1 was:

-   -   5′-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3′ (SEQ ID NO:1)        The sequence of reverse oligonucleotide 2 was:    -   5′-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3′ (SEQ ID NO:2)

PCR was then performed as follows:

a. Denature 92° C.,  5 minutes b.  3 cycles of: Denature 92° C., 30seconds Anneal 59° C., 30 seconds Extend 72° C., 60 seconds c.  3 cyclesof: Denature 92° C., 30 seconds Anneal 57° C., 30 seconds Extend 72° C.,60 seconds d. 25 cycles of: Denature 92° C., 30 seconds Anneal 55° C.,30 seconds Extend 72° C., 60 seconds e. Hold  4° C.

The underlined regions of the oligonucleotides annealed to the ADHpromoter region and the amylase region, respectively, and amplified a307 bp region from vector pSST-AMY.0 when no insert was present.Typically, the first 18 nucleotides of the 5′ end of theseoligonucleotides contained annealing sites for the sequencing primers.Thus, the total product of the PCR reaction from an empty vector was 343bp. However, signal sequence-fused cDNA resulted in considerably longernucleotide sequences.

Following the PCR, an aliquot of the reaction (5 μl) was examined byagarose gel electrophoresis in a 1% agarose gel using a Tris-Borate-EDTA(TBE) buffering system as described by Sambrook et al., supra. Clonesresulting in a single strong PCR product larger than 400 bp were furtheranalyzed by DNA sequencing after purification with a 96 Qiaquick PCRclean-up column (Qiagen Inc., Chatsworth, Calif.).

Example 3 Isolation of cDNA Clones Using Signal Algorithm Analysis

Various polypeptide-encoding nucleic acid sequences were identified byapplying a proprietary signal sequence finding algorithm developed byGenentech, Inc. (South San Francisco, Calif.) upon ESTs as well asclustered and assembled EST fragments from public (e.g., GcnBank) and/orprivate (LIFESEQ®, Incyte Pharmaceuticals, Inc., Palo Alto, Calif.)databases. The signal sequence algorithm computes a secretion signalscore based on the character of the DNA nucleotides surrounding thefirst and optionally the second methionine codon(s) (ATG) at the 5′-endof the sequence or sequence fragment under consideration. Thenucleotides following the first ATG must code for at least 35unambiguous amino acids without any stop codons. If the first ATG hasthe required amino acids, the second is not examined. If neither meetsthe requirement, the candidate sequence is not scored. In order todetermine whether the EST sequence contains an authentic signalsequence, the DNA and corresponding amino acid sequences surrounding theATG codon are scored using a set of seven sensors (evaluationparameters) known to be associated with secretion signals. Use of thisalgorithm resulted in the identification of numerouspolypeptide-encoding nucleic acid sequences.

Example 4 Isolation of cDNA Clones Encoding Human PRO1560

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein as DNA17409. Based on the DNA17409 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1560.

DNA sequencing of the isolated clones isolated as described above gavethe full-length DNA sequence for DNA19902-1669 [FIG. 1, SEQ ID NO:3];and the derived protein sequence for PRO1560.

The entire coding sequence of DNA19902-1669 is included in FIG. 1 (SEQID NO:3). Clone DNA19902-1669 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 41-43,and an apparent stop codon at nucleotide positions 776-778. Thepredicted polypeptide precursor is 245 amino acids long. The approximatelocations of the signal peptide, transmembrane domains, N-glycosylationsites, N-myristoylation sites, tyrosine kinase phosphorylation sites,and membrane lipoprotein lipid attachment sites are also indicated inFIG. 2. Clone DNA19902-1669 has been deposited with the ATCC and isassigned ATCC deposit no. 203454. The full-length PRO1560 protein shownin FIG. 2 has an estimated molecular weight of about 27,563 daltons anda pI of about 8.36.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 2 (SEQ ID NO:4), revealed sequence identity between thePRO1560 amino acid sequence and the following Dayhoff sequences:AF053453_(—)1, AF053454_(—)1, A15_HUMAN, AF054840_(—)1, CD63_HUMAN,AF065389_(—)1, AF054838_(—)1, AF089749_(—)1, P_R27525, and P_R86834.

Example 5 Isolation of cDNA Clones Encoding Human PRO444

A cDNA sequence isolated in the amylase screen described in Example 2above was designated DNA13121. Based upon this sequence, probes weregenerated and used to screen a human fetal lung library (LIB25) preparedas described in paragraph 1 of Example 2 above. The cloning vector waspRK5B (pRK5B is a precursor of pRK5D that does not contain the SfiIsite; see, Holmes et al., Science, 253: 1278-1280 (1991)), and the cDNAsize cut was less than 2800 bp.

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 608-610 and ending at the stop codon found at nucleotidepositions 959-961 (FIG. 3, SEQ ID NO:5). The predicted polypeptideprecursor is 117 amino acids long, has a calculated molecular weight ofapproximately 12,692 daltons and an estimated pI of approximately 7.50.Analysis of the full-length PRO444 sequence shown in FIG. 4 (SEQ IDNO:6) evidences the presence of a signal peptide at amino acid 1 toabout amino acid 16. An analysis of the Dayhoff database (version 35.45SwissProt 35) evidenced homology between the PRO444 amino acid sequenceand the following Dayhoff sequences: CEF44D12_(—)8, P_R88452,YNE1_CAEEL, A47312, AF009957_(—)1, and A06133_(—)1. Clone DNA26846-1397was deposited with the ATCC on Oct. 27, 1998 and is assigned ATCCdeposit no. 203406.

Example 6 Isolation of cDNA Clones Encoding Human PRO1018

A cDNA clone (DNA56107-1415) encoding a native human PRO1018 polypeptidewas identified by a yeast screen, in a human ovary tumor cDNA librarythat preferentially represents the 5′ ends of the primary cDNA clones.The yeast screen employed identified a single EST clone designatedherein as DNA41000. The DNA41000 sequence was then compared to variousEST databases including public EST databases (e.g., GenBank), and aproprietary EST database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto,Calif.) to identify homologous EST sequences. The comparison wasperformed using the computer program BLAST or BLAST2 [Altschul et al.,Methods in Enzymology, 266: 460-480 (1996)]. Those comparisons resultingin a BLAST score of 70 (or in some cases, 90) or greater that did notencode known proteins were clustered and assembled into a consensus DNAsequence with the program “phrap” (Phil Green, University of Washington,Seattle, Wash.). This consensus sequence is herein designated DNA44449.Oligonucleotide primers based upon the DNA44449 sequence were thensynthesized and employed to screen a human ovary tumor cDNA librarywhich resulted in the identification of the DNA56107-1415 clone shown inFIG. 5.

The full-length DNA56107-1415 clone shown in FIG. 5 contains a singleopen reading frame with an apparent translational initiation site atnucleotide positions 129-131 and ending at the stop codon at nucleotidepositions 696-698 (FIG. 5). The predicted polypeptide precursor is 189amino acids long (FIG. 6). Analysis of the full-length PRO1018 sequenceshown in FIG. 6 (SEQ ID NO:8) evidences the presence of the following: asignal peptide from about amino acid 1 to about amino acid 24,transmembrane domains from about amino acid 86 to about amino acid 103and from about amino acid 60 to about amino acid 75 and an amino acidsequence block having homology to G-protein coupled receptor proteinsfrom about amino acid 44 to about amino acid 84. Clone DNA56107-1415 hasbeen deposited with ATCC on Oct. 27, 1998 and is assigned ATCC depositno. 203405.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 6 (SEQ ID NO:8), evidenced significant homology betweenthe PRO1018 amino acid sequence and the following Dayhoff sequences:CEB0399_(—)4, S59764, YHDT_HAEIN and AE000675_(—)3.

Example 7 Isolation of cDNA Clones Encoding Human PRO1773

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA49797. Based upon an observed homology between theDNA49797 consensus sequence and an EST sequence contained within IncyteEST clone no. 509434, Incyte EST clone no.509434 was purchased and itsinsert obtained and sequenced. That sequence is herein shown in FIG. 7and is designated DNA56406-1704.

The entire nucleotide sequence of DNA56406-1704 is shown in FIG. 7 (SEQID NO:9). Clone DNA56406-1704 contains a single open reading frame withan apparent translational initiation site at nucleotide positions111-113 and ending at the stop codon at nucleotide positions 1068-1070(FIG. 7). The predicted polypeptide precursor is 319 amino acids long(FIG. 8). The full-length PRO1773 protein shown in FIG. 8 has anestimated molecular weight of about 35,227 daltons and a pI of about8.97. Analysis of the full-length PRO1773 sequence shown in FIG. 8 (SEQID NO:10) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 17, a transmembrane domain fromabout amino acid 136 to about amino acid 152, potential N-glycosylationsites from about amino acid 161 to about amino acid 164, from aboutamino acid 187 to about amino acid 190 and from about amino acid 253 toabout amino acid 256, a glycosaminoglycan attachment site from aboutamino acid 39 to about amino acid 42 and potential N-myristolation sitesfrom about amino acid 36 to about amino acid 41, from about amino acid42 to about amino acid 47, from about amino acid 108 to about amino acid113, from about amino acid 166 to about amino acid 171, from about aminoacid 198 to about amino acid 203 and from about amino acid 207 to aboutamino acid 212. Clone DNA56406-1704 has been deposited with ATCC on Nov.17, 1998 and is assigned ATCC deposit no. 203478.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 8 (SEQ ID NO:10), evidenced significant homology betweenthe PRO1773 amino acid sequence and the following Dayhoff sequences:ROH2_RAT, ROH3_RAT, AF030513_(—)1, ROH1R_RAT, AF056194^(—)1,AF057034_(—)1, P_W18337, P_W18328, BDH_HUMAN and BDH_RAT.

Example 8 Isolation of cDNA Clones Encoding Human PRO1477

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA52641. Based on the DNA52641 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO240.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′-CGCCAGAAGGGCGTGATTGACGTC-3′ (SEQ ID NO:13)-   reverse PCR primer 5′-CCATCCTTCTTCCCAGACAGGCCG-3′ (SEQ ID NO:14)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA52641 sequence which had the    following nucleotide sequence-   hybridization probe    5′-GAAGCCTGTGTCCAGGTCCTTCAGTGAGTGGTTTGGCCTCGGTC-3′ (SEQ ID NO:15)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO240 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1477 (designated herein as DNA56529-1647[FIG. 9, SEQ ID NO:11]; and the derived protein sequence for PRO1477.

The entire nucleotide sequence of DNA56529-1647 is shown in FIG. 9 (SEQID NO:11). Clone DNA56529-1647 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 23-25and ending at the stop codon at nucleotide positions 2120-2122 (FIG. 9).The predicted polypeptide precursor is 699 amino acids long (FIG. 10).The full-length PRO240 protein shown in FIG. 10 has an estimatedmolecular weight of about 79,553 daltons and a pI of about 7.83.Analysis of the full-length PRO1477 sequence shown in FIG. 10 (SEQ IDNO:12) evidences the presence of the following: transmembrane domainsfrom about amino acid 21 to about amino acid 40 and from about aminoacid 84 to about amino acid 105. Clone DNA56529-1647 has been depositedwith ATCC on Sep. 29, 1998 and is assigned ATCC deposit no. 203293.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 10 (SEQ ID NO:12), evidenced significant homology betweenthe PRO1477 amino acid sequence and the following Dayhoff sequences:CELT03G11_(—)1, CEZC410_(—)4, A54408, SSMAN9MAN_(—)1, GEN12643,GEN12642, AF027156_(—)1, P_W46900, SPAC23A1_(—)4 and DMC86E4_(—)5.

Example 9 Isolation of cDNA Clones Encoding Human PRO1478

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “DNA52719”. Based on the DNA52719 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1478.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′GCGAACGCTTCGAGGAGTCCTGG3′ (SEQ ID NO:18); and-   reverse PCR primer 5′GCAGTGCGGGAAGCCACATGGTAC3′ (SEQ ID NO:19).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA52719 sequence which had the followingnucleotide sequence:

-   hybridization probe    5′CTTCCTGAGCAGGAAGAAGATCCGGCACCACATCTACGTGCTCAAC3′ (SEQ ID NO:20).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1478 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1478 and the derived protein sequencefor PRO1478.

The entire coding sequence of PRO1418 is included in FIG. 11 (SEQ IDNO:16). Clone DNA56531-1648 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 77-79 andan apparent stop codon at nucleotidc positions 1058-1060 of SEQ IDNO:16. The predicted polypeptide precursor is 327 amino acids long. Thetype II transmembrane sequence is believed to be at about amino acids29-49 of SEQ ID NO:17, and an N-glycosylation site is believed to be atabout amino acids 154-157 of SEQ ID NO:17. Clone DNA56531-1648 has beendeposited with ATCC and is assigned ATCC deposit no. 203286. Thefull-length PRO1478 protein shown in FIG. 12 has an estimated molecularweight of about 37,406 daltons and a pI of about 9.3.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 12 (SEQ ID NO:17), revealed sequence identity between thePRO1478 amino acid sequence and the following Dayhoff sequences:YNJ4_CAEEL, P_R55706, A38781_(—)1, NALS_MOUSE, HUMHGT_(—)1,AF048687_(—)1, CFW02B12_(—)11, Y09F_MYCTU, FOJO_DROME, and G01936.

Example 10 Isolation of cDNA Clones Encoding Human PRO831

DNA56862-1343 was identified by applying the proprietary signal sequencefinding algorithm described in Example 3 above. Use of the abovedescribed signal sequence algorithm allowed identification of an ESTcluster sequence from the Incyte database, designated Incyte clustersequence no. 25507. This EST cluster sequence was then compared to avariety of expressed sequence tag (EST) databases which included publicEST databases (e.g., GenBank) and a proprietary EST DNA database(Lifeseq®, Incyte Pharmaceuticals, Palo Alto, Calif.) to identifyexisting homologies. The homology search was performed using thecomputer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology266: 460-480 (1996)). Those comparisons resulting in a BLAST score of 70(or in some cases 90) or greater that did not encode known proteins wereclustered and assembled into a consensus DNA sequence with the program“phrap” (Phil Green, University of Washington). The consensus sequenceobtained therefrom is herein designated as DNA55714.

In light of the sequence homology between the DNA55714 sequence and anEST sequence contained within the Merck EST clone no. AA099445, theMerck EST clone no. AA099445 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 13 and is herein designated as DNA56862-1343.

Clone DNA56862-1343 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 40-42 andending at the stop codon at nucleotide positions 259-261 (FIG. 13). Thepredicted polypeptide precursor is 73 amino acids long (FIG. 14). Thefull-length PRO831 protein shown in FIG. 14 has an estimated molecularweight of about 7,879 daltons and a pI of about 7.21. Analysis of thefull-length PRO831 sequence shown in FIG. 14 (SEQ ID NO:22) evidencesthe presence of the following: a signal peptide from about amino acid 1to about amino acid 15 and an amino acid sequence block having homologyto growth factor and cytokine receptor family proteins from about aminoacid 3 to about amino acid 18. Clone DNA56862-1343 has been depositedwith ATCC on Sep. 1, 1998 and is assigned ATCC deposit no. 203174.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAS12 sequence alignment analysis of the full-length sequenceshown in FIG. 14 (SEQ ID NO:22), evidenced significant homology betweenthe PRO831 amino acid sequence and the following Dayhoff sequences:P_W30724. HUMPPA_(—)1, AF022238_(—)1, 4HHB_C, P_R39727, P_R39728,TRYT_MERUN, GPR5_HUMAN, AB010266_(—)3 and HSBCL3S2_(—)1.

Example 11 Isolation of cDNA Clones Encoding Human PRO1113

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “DNA34025”. Based on the DNA34025 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1113.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′GAGGACTCACCAATCTGGTTCGGC3′ (SEQ ID NO:25); and-   reverse PCR primer 5′AACTGGAAAGGAAGGCTGTCTCCC3′ (SEQ ID NO:26).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA34025 sequence which had the followingnucleotide sequence:

-   hybridization probe 5′GTAAAGGAGA    AGAACATCACGGTACGGGATACCAGGTGTGTTTATCCTAA3′ (SEQ ID NO:27).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1113 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal kidney.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1113 (designated herein as DNA57254-1477[FIG. 15, SEQ ID NO:23]; and the derived protein sequence for PRO1113.

The entire coding sequence of PRO1113 is shown in FIG. 15 (SEQ IDNO:23). Clone DNA57254-1477 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 214-216,and an apparent stop codon at nucleotide positions 2062-2064 of SEQ IDNO:23. The predicted polypeptide precursor is 616 amino acids long. Thetransmembrane domain (type II) is believed to be at about amino acids13-40 of SEQ ID NO:24. The N-glycosylation sites and N-myristoylationsites are indicated in FIG. 16. Clone DNA57254-1477 has been depositedwith the ATCC and is assigned ATCC deposit no. 203289. The full-lengthPRO1113 protein shown in FIG. 16 has an estimated molecular weight ofabout 68,243 daltons and a pI of about 8.66.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 16 (SEQ ID NO:24), revealed sequence identity between thePRO1113 amino acid sequence and the following Dayhoff sequences (dataincorporated herein): D86983_(—)1, A58532, SLIT_DROME, AB007865_(—)1,AC004142_(—)1, CELT21D12_(—)8, AB003184_(—)1, DMU42767_(—)1,MUSLRRP_(—)1 and GPCR_LYMST.

Example 12 Isolation of cDNA Clones Encoding Human PRO1194

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs was derived from a human pinealgland library. The homology search was performed using the computerprogram BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (orin some cases 90) or greater that did not encode known proteins wereclustered and assembled into a consensus DNA sequence with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.). Theconsensus sequence obtained therefrom is herein designated DNA56511.

In light of the sequence homology between the DNA56511 sequence and anEST contained within the Merck EST AA069568, the clone 382736 whichincludes this EST was purchased and the cDNA insert was obtained andsequenced. The sequence of this cDNA insert is shown in FIG. 17 and isherein designated as DNA57841-1522.

The full length clone shown in FIG. 17 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 9-11 and ending at the stop codon found at nucleotidepositions 252-254 (FIG. 17; SEQ ID NO:28). The predicted polypeptideprecursor (FIG. 18, SEQ ID NO:29) is 81 amino acids long. The signalpeptide is at about amino acids 1-21 of SEQ ID NO:29. PRO1194 has acalculated molecular weight of approximately 9,223 daltons and anestimated pI of approximately 10.47. Clone DNA57841-1522 was depositedwith the ATCC on Nov. 3, 1998 and is assigned ATCC deposit no. 203458.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 18 (SEQ ID NO:29), revealed sequence identity between thePRO1194 amino acid sequence and the following Dayhoff sequences:PT17_YEAST, RR2_CHLVU, CEK12F2_(—)1, S22452, S76705, AF031898_(—)7,A4_DROME, AF038931_(—)1, E49905, and GSPL_AERHY.

Example 13 Isolation of cDNA Clones Encoding Human PRO1110

A cDNA clone (DNA58727-1474) encoding a native human PRO1110 polypeptidewas identified by a yeast screen, in a human fetal kidney cDNA librarythat preferentially represents the 5′ ends of the primary cDNA clones.The yeast screen employed identified a single EST clone designatedherein as DNA45566. The DNA45566 sequence was then compared to variousEST databases including public EST databases (e.g., GenBank), and aproprietary EST database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto,Calif.) to identify homologous EST sequences. The comparison wasperformed using the computer program BLAST or BLAST2 [Altschul et al.,Methods in Enzymology, 266: 460-480 (1996)]. Those comparisons resultingin a BLAST score of 70 (or in some cases, 90) or greater that did notencode known proteins were clustered and assembled into a consensus DNAsequence with the program “phrap” (Phil Green, University of Washington,Seattle, Wash.). This consensus sequence is herein designated DNA46965.Oligonucleotide primers based upon the DNA46965 sequence were thensynthesized and employed to screen a human SK-Lu-1 adenocarcinoma cDNAlibrary (LIB247) which resulted in the identification of theDNA58727-1474 clone shown in FIG. 19.

The full-length DNA58727-1474 clone shown in FIG. 19 contains a singleopen reading frame with an apparent translational initiation site atnucleotide positions 131-133 and ending at the stop codon at nucleotidepositions 1097-1099 (FIG. 19). The predicted polypeptide precursor is322 amino acids long (FIG. 20). The full-length PRO1110 protein shown inFIG. 20 has an estimated molecular weight of about 35,274 daltons and apI of about 8.57. Analysis of the full-length PRO1110 sequence shown inFIG. 20 (SEQ ID NO:31) evidences the presence of the following:transmembrane domains from about amino acid 41 to about amino acid 60,from about amino acid 66 to about amino acid 85, from about amino acid101 to about amino acid 120, from about amino acid 137 to about aminoacid 153, from about amino acid 171 to about amino acid 192, from aboutamino acid 205 to about amino acid 226, from about amino acid 235 toabout amino acid 255 and from about amino acid 294 to about amino acid312, a potential N-glycosylation site from about amino acid 6 to aboutamino acid 69, and a glycosaminoglycan attachment site from about aminoacid 18 to about amino acid 21. Clone DNA58727-1474 has been depositedwith ATCC on Sep. 1, 1998 and is assigned ATCC deposit no. 203171.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 20 (SEQ ID NO:31), evidenced significant homology betweenthe PRO1116 amino acid sequence and the following Dayhoff sequences:MMMYELUPR_(—)1, P_R99799, MAL_HUMAN, P_P80929, RNMALGENE_(—)1, S68406,PLLP_RAT, MMMALPROT_(—)1, I38891 and S55622.

Example 14 Isolation of cDNA Clones Encoding Human PRO1378

An initial DNA sequence referred to herein as DNA51941 was identifiedusing a yeast screen, in a human bone marrow cDNA library thatpreferentially represents the 5′ ends of the primary cDNA clones. Basedon the DNA51941 sequence, the following oligonucleotides weresynthesized for use as probes to isolate a clone of the full-lengthcoding sequence for PRO1377 from a bone marrow cDNA library:TGTCCTTTGTCCCAGACTTCTGTCC (SEQ ID NO: 34),CTGGATGCTAATGTGTCCAGTAAATGATCCCCTTATCCCGTCGCGATGCT (SEQ ID NO:35);TTCCACTCAATGAGGTGAGCCACTC (SEQ ID NO:36); GGCGAGCCCTAACTATCCAGGAG (SEQID NO:37): GGAGATCGCTGCGCTGGCCAGGTCCTCCCTGCATGGTAT (SEQ ID NO:38); andCTGCTGCAAAGCGAGCCTCTTG (SEQ ID NO:39).

The full length DNA58730-1607 clone shown in FIG. 21 contained a singleopen reading frame with an apparent translational initiation site atnucleotide positions 1365 to 1367 and ending at the stop codon found atnucleotide positions 2370 to 2372 (FIG. 21; SEQ ID NO:32). The predictedpolypeptide precursor (FIG. 22, SEQ ID NO:33) is 335 amino acids long,with a signal peptide sequence at about amino acids 1-15. PRO1378 has acalculated molecular weight of approximately 36,108 daltons and anestimated pI of approximately 4.51.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 22 (SEQ ID NO:33), revealed some homology between thePRO1378 amino acid sequence and the following Dayhoff sequences:ICAL_RABIT, SP2_HUMAN, SIIPSPRBB_(—)1, SP23_HUMAN, P_W08158, andP_W08150.

Clone DNA58730-1607 was deposited with the ATCC on Sep. 15, 1998, and isassigned ATCC deposit no. 203221.

Example 15 Isolation of cDNA Clones Encoding Human PRO1481

An initial DNA sequence, referred to herein as DNA53254, was identifiedusing a yeast screen, in a human fetal kidney cDNA library thatpreferentially represents the 5′ ends of the primary cDNA clones. Basedon the DNA53254 sequence, oligonucleotides were synthesized for use asprobes (or primers) to isolate a clone of the full-length codingsequence for PRO1481 from a human fetal kidney cDNA library.

The full length DNA58732-1650 clone shown in FIG. 23 contained a singleopen reading frame with an apparent translational initiation site atnucleotide positions 320-322 and ending at the stop codon found atnucleotide positions 1322-1324 (FIG. 23; SEQ ID NO:40). The predictedpolypeptide precursor (FIG. 24, SEQ ID NO:41) is 334 amino acids long.The signal peptide is at about amino acids 1-23, and a transmembranedomain is at about amino acids 235-262 of SEQ ID NO:41. TheN-glycosylation sites are indicated in FIG. 24. PRO1481 has a calculatedmolecular weight of approximately 36,294 daltons and an estimated pI ofapproximately 4.98. Clone DNA58732-1650 has been deposited with the ATCCand is assigned ATCC deposit no. 203290.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 24 (SEQ ID NO:41), revealed sequence identity between thePRO1481 amino acid sequence and the following Dayhoff sequences (dataincorporated herein): YN23_YEAST, S67770, H36857, YLU2_PICAN, GEN12881,CVY15035_(—)28, YM96_YEAST, ESC1_SCHPO, CELZK783_(—)1 and S59310.

Example 16 Isolation of cDNA Clones Encoding Human PRO1189

A cDNA sequence isolated in the amylase screen described in Example 2above is herein designated DNA41784. The DNA41784 sequence was thencompared to a variety of expressed sequence tag (EST) databases whichincluded public EST databases (e.g., GenBank) and proprietary EST DNAdatabases (LIFESEQTM, Incyte Pharmaceuticals, Palo Alto, Calif.; andGenentech, South San Francisco, Calif.) to identify existing homologies.The homology search was performed using the computer program BLAST orBLAST2 (Altshul et al., Methods in Enzymology 266: 460-480 (1996)).Those comparisons resulting in a BLAST score of 70 (or in some cases 90)or greater that did not encode known proteins were clustered andassembled into consensus DNA sequences with the program “phrap” (PhilGreen, University of Washington, Seattle, Wash.). The consensus sequenceobtained therefrom is herein designated DNA45499.

Based on the DNA45499 sequence, oligonucleotide probes were generatedand used to screen a human bone marrow library prepared as described inparagraph 1 of Example 2 above. The cloning vector was pRK5B (pRK5B is aprecursor of pRK5D that does not contain the SfiI site; see, Holmes etal., Science, 253: 1278-1280 (1991)), and the cDNA size cut was lessthan 2800 bp.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (45499.f1) 5′-GAAAGACACGACACAGCAGCTTGC-3′ (SEQ ID    NO:44)-   forward PCR primer (45499.f2) 5′-GGGAACTGCTATCTGATGCC-3′ (SEQ ID    NO:45)-   forward PCR primer (45499.f3) 5′-CAGGATCTCCTCTTGCAGTCTGCAGC-3′ (SEQ    ID NO:46)-   reverse PCR primer (45499.r1) 5′CTTCTCGAACCACATAAGTTTGAGGCAG-3′ (SEQ    ID NO:47)-   reverse PCR primer (45499.r2) 5′-CACGATTCCCTCCACAGCAACTGGG-3′ (SEQ    ID NO:48).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the DNA45499 sequence which had the followingnucleotide sequence:

-   hybridization probe (45499.p1)    5′-CGCCTTACCGCGCAGCCCGAAGATTCACTATGGTGAAAATCGCCTTCAAT-3′ (SEQ ID    NO:230).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1189 gene using the probe oligonucleotideand one of the PCR primers.

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 79-81, and a stop signal at nucleotide positions 868-870 (FIG.25; SEQ ID NO:42). The predicted polypeptide precursor is 263 aminoacids long has a calculated molecular weight of approximately 29,741daltons and an estimated pI of approximately 5.74. Additional featuresinclude a type II transmembrane domain at about amino acids 53-75 and apotential N-glycosylation site at about amino acids 166-169.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 26 (SEQ ID NO:43), evidenced significant homology betweenthe PRO1189 amino acid sequence and Dayhoff sequences MUSE25A_(—)1 andHS696H22_(—)1. Additionally, some homology was revealed between thePRO1189 amino acid sequence and the following Dayhoff sequences:AF017985_(—)1, CBRG01D9_(—)2, 179662, and CHPDRBAG_(—)1.

Clone DNA58828-1519 has been deposited with ATCC and is assigned ATCCdeposit no. 203172.

Example 17 Isolation of cDNA Clones Encoding Human PRO1415

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 150918. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA55720.

In light of the sequence homology between the DNA55720 sequence and anEST sequence contained within the Incyte EST clone no. 4081476, theIncyte EST clone no. 4081476 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 27 and is herein designated as DNA58852-1637.

Clone DNA58852-1637 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 148-150and ending at the stop codon at nucleotide positions 997-999 (FIG. 27).The predicted polypeptide precursor is 283 amino acids long (FIG. 28).The full-length PRO1415 protein shown in FIG. 28 has an estimatedmolecular weight of about 29,191 daltons and a pI of about 4.52.Analysis of the full-length PRO1415 sequence shown in FIG. 28 (SEQ IDNO:50) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 25, a transmembrane domain fromabout amino acid 94 to about amino acid 118 and potentialN-myristolation sites from about amino acid 18 to about amino acid 23,from about amino acid 40 to about amino acid 45, from about amino acid46 to about amino acid 51, from about amino acid 145 to about amino acid150, from about amino acid 192 to about amino acid 197, from about aminoacid 193 to about amino acid 198, from about amino acid 211 to aboutamino acid 216, from about amino acid 238 to about amino acid 243 andfrom about amino acid 242 to about amino acid 247. Clone DNA58852-1637has been deposited with ATCC on Sep. 22, 1998 and is assigned ATCCdeposit no. 203271.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 28 (SEQ ID NO:50), evidenced significant homology betweenthe PRO1415 amino acid sequence and the following Dayhoff sequences:HSU66616_(—)1, P_W24017, A38219, CD30_HUMAN, HSU78971_(—)1, P_W22214,NFM_HUMAN, ADH1_ASPFL, PAU93274_(—)5 and CENB_MOUSE.

Example 18 Isolation of cDNA Clones Encoding Human PRO1411

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from an Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs were derived from a thryroid tissuelibrary. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). The consensussequence obtained therefrom is herein designated DNA56013.

In light of the sequence homology between the DNA56013 sequence and anEST sequence contained within the Incyte EST 1444225, the cloneincluding this EST was purchased and the cDNA insert was obtained andsequenced. The sequence of this cDNA insert is shown in FIG. 29 and isherein designated as DNA59212-1627.

The full length clone shown in FIG. 29 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 184-186 and ending at the stop codon found at nucleotidepositions 1504-1506 (FIG. 29; SEQ ID NO:51). The predicted polypeptideprecursor (FIG. 30, SEQ ID NO:52) is 440 amino acids long. The signalpeptide is at about amino acids 1-21, and the cell attachment site is atabout amino acids 301-303 of SEQ ID NO:52. PRO1411 has a calculatedmolecular weight of approximately 42,208 daltons and an estimated pI ofapproximately 6.36. Clone DNA59212-1627 was deposited with the ATCC onSep. 9, 1998 and is assigned ATCC deposit no. 203245.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 30 (SEQ ID NO:52), revealed sequence identity between thePRO1411 amino acid sequence and the following Dayhoff sequences (datafrom database incorporated herein): MTV023_(—)19, P_R05307, P_W26348,P_P82962, AF000949_(—)1, EBN1_EBV, P_R95107, GRP2_PHAVU, P_R81318, andS74439_(—)1.

Example 19 Isolation of cDNA Clones Encoding Human PRO1295

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs was derived from a thymus tissuelibrary. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). The consensussequence obtained therefrom is herein designated DNA56262.

In light of the sequence homology between the DNA56262 sequence and anEST contained within the Incyte EST 3743334, the clone including thisEST was purchased and the cDNA insert was obtained and sequenced. Thesequence of this cDNA insert is shown in FIG. 31 and is hereindesignated as DNA59218-1559.

The full length clone shown in FIG. 31 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 207-209 and ending at the stop codon found at nucleotidepositions 1047-1049 (FIG. 31; SEQ ID NO:53). The predicted polypeptideprecursor (FIG. 32, SEQ ID NO:54) is 280 amino acids long. The signalpeptide is at about amino acids 1-18 of SEQ ID NO:54. A targeting signaland N-glycosylation site arc also indicated in FIG. 54. PRO1295 has acalculated molecular weight of approximately 30,163 daltons and anestimated pI of approximately 6.87. Clone DNA59218-1559 was depositedwith the ATCC on Sep. 29, 1998 and is assigned ATCC deposit no. 203287.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 32 (SEQ ID NO:54), revealed sequence identity between thePRO1295 amino acid sequence and the following Dayhoff sequences (dataincorporated herein): AB011099_(—)1. ILVE_MYCTU, ATECR_(—)2,AF010496_(—)27, P_R15346, S37191, PER_DROMS, L2MU_ADECC and P_W34238.

Example 20 Isolation of cDNA Clones Encoding Human PRO1359

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from an Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESFQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs was derived from a sigmoid colontissue library. The homology search was performed using the computerprogram BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (orin some cases 90) or greater that did not encode known proteins wereclustered and assembled into a consensus DNA sequence with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.). Theconsensus sequence obtained therefrom is herein designated DNA56263.

In light of the sequence homology between the DNA56263 sequence and theIncyte EST 1931418, the clone including this EST was purchased and thecDNA insert was obtained and sequenced. The sequence of this cDNA insertis shown in FIG. 33 and is herein designated as DNA59219-1613.

The full length clone shown in FIG. 33 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 184-186 and ending at the stop codon found at nucleotidepositions 1081-1083 (FIG. 33; SEQ ID NO:55). The predicted polypeptideprecursor (FIG. 34, SEQ ID NO:56) is 299 amino acids long. Thetransmembrane domain is at about amino acids 9-31 of SEQ ID NO:56.N-gylcosylation sites are at about amino acids 64-67 and 115-118 of SEQID NO:56. PRO1359 has a calculated molecular weight of approximately34,291 daltons and an estimated pI of approximately 9.87. CloneDNA59219-1613 was deposited with the ATCC on Sep. 15, 1998 and isassigned ATCC deposit no. 203220.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 34 (SEQ ID NO:56), revealed sequence identity between thePRO1359 amino acid sequence and the following Dayhoff sequences (dataincorporated herein): GEM14384, P_R78622, A23699_(—)1, P_R65244, A54898,AF059321_(—)1, RNU55938_(—)1, BTRNAST6_(—)1, P_R75199 and P_R63216.

Example 21 Isolation of cDNA Clones Encoding Human PRO1190

The method described in Example 1 above allowed the identification of asingle Merck/Washington University EST sequence, EST no. AA339802, whichis designated herein as “DNA53943”. Based on the DNA53943 sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1190.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: (53943.f1) GGGAAACACAGCAGTCATTGCCTGC (SEQ ID    NO:59)-   reverse PCR primer: (53943.r1) GCACACGTAGCCTGTCGCTGGAGC (SEQ ID    NO:60)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the DNA53943 sequence which had the followingnucleotide sequence:

-   hybridization probe: (53943.p1)    CACCCCAAAGCCCAGGTCCGGTACAGCGTCAAACAAGAGTGG (SEQ ID NO:61)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1190 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human bone marrow.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1190 (designated herein as DNA59586-1520[FIG. 35, SEQ ID NO:57]; and the derived protein sequence for PRO1190.

The entire coding sequence of PRO1190 is shown in FIG. 35 (SEQ IDNO:57). Clone DNA59586-1520 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 340-342and an apparent stop codon at nucleotide positions 3685-3687. Thepredicted polypeptide precursor is 1115 amino acids long. Thefull-length PRO1190 protein shown in FIG. 36 has an estimated molecularweight of about 121,188 daltons and a pI of about 7.07. Other featuresof the PRO1190protein include: two transmembrane domains at amino acids16-30 and 854-879; a cytochrome P450 cystein heme-iron ligand signatureat amino acids 1051-1060; an N-6 adenine-specific DNA methylasessignature at amino acids 1045-1051; and potential N-glycosylation sitesat amino acids 65-68, 76-79, 98-101, 189-192, 275-278, 518-521, 726-729,and 760-763. Clone DNA59586-1520 was deposited with the ATCC on Sep. 29,1998, and is assigned ATCC deposit no. 203288.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 36 (SEQ ID NO:58), revealed homology between the PRO1190amino acid sequence and the following Dayhoff sequences: AF004840_(—)1,AF004841_(—)1, AF026465_(—)1, HSU72391_(—)1, P_R13144, AXO1_HUMAN,GEN13349, I58164, D87212_(—)1, A53449, and D86983_(—)1, and KIAA0230.

Example 22 Isolation of cDNA Clones Encoding Human PRO1772

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA45120. Based on the DNA45120 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1772.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (45120.f1) 5′-CCTTCACCTGCAGTACACCATGGGC-3′ (SEQ    ID NO:64)-   reverse PCR primer (45120.r1) 5′-GTCACACACAGCTCTGGCAGCTGAG-3′ (SEQ    ID NO:65)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA45120 sequence which had the    following nucleotide sequence-   hybridization probe (45120.p1)    5′-CCAAGTTCAGACACCACATGTACACCAACGTCAGCGGATTGACAAGC-3′ (SEQ ID NO:66)

RNA for construction of the cDNA libraries was isolated from human bonemarrow tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1772 (designated herein as DNA59817-1703[FIG. 37, SEQ ID NO:62]; and the derived protein sequence for PRO1772.

The entire nucleotide sequence of DNA59817-1703 is shown in FIG. 37 (SEQID NO:62). Clone DNA59817-1703 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 93-95and ending at the stop codon at nucleotide positions 1554-1556 (FIG.37). The predicted polypeptide precursor is 487 amino acids long (FIG.38). The full-length PRO1772 protein shown in FIG. 38 has an estimatedmolecular weight of about 53,569 daltons and a pI of about 7.68.Analysis of the full-length PRO1772 sequence shown in FIG. 38 (SEQ IDNO:63) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 36, a transmembrane domain fromabout amino acid 313 to about amino acid 331, potential N-glycosylationsites from about amino acid 119 to about amino acid 122, from aboutamino acid 184 to about amino acid 187, from about amino acid 243 toabout amino acid 246 and from about amino acid 333 to about amino acid336, potential N-myristolation sites from about amino acid 41 to aboutamino acid 46, from about amino acid 59 to about amino acid 64, fromabout amino acid 73 to about amino acid 78, from about amino acid 133 toabout amino acid 138, from about amino acid 182 to about amino acid 187,from about amino acid 194 to about amino acid 199, from about amino acid324 to about amino acid 329, from about amino acid 354 to about aminoacid 359, from about amino acid 357 to about amino acid 362, from aboutamino acid 394 to about amino acid 399, from about amino acid 427 toabout amino acid 432 and from about amino acid 472 to about amino acid477 and a prokaryotic membrane lipoprotein lipid attachment site fromabout amino acid 136 to about amino acid 146. Clone DNA59817-1703 hasbeen deposited with ATCC on Nov. 17, 1998 and is assigned ATCC depositno. 203470.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 38 (SEQ ID NO:63), evidenced significant homology betweenthe PRO1772 amino acid sequence and the following Dayhoff sequences:P_R30823, MDP1_PIG, MDP1_HUMAN, P_R13857, P_R53920, MDP1_MOUSE,P_R30822, JC4222, CELF52C6_(—)2 and MYV027_(—)13.

Example 23 Isolation of cDNA Clones Encoding Human PRO1248

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 7494. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzmmology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56056.

In light of the sequence homology between the DNA56056 sequence and anEST contained within the Merck EST clone no. AA404441, the Merck ESTclone no. AA404441 was purchased and the cDNA insert was obtained andsequenced. The sequence of this cDNA insert is shown in FIG. 39 and isherein designated as DNA60278-1530.

Clone DNA60278-1530 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 122-124and ending at the stop codon at nucleotide positions 671-673 (FIG. 39).The predicted polypeptide precursor is 183 amino acids long (FIG. 40).The full-length PRO1248 protein shown in FIG. 40 has an estimatedmolecular weight of about 20,574 daltons and a pI of about 6.60.Analysis of the full-length PRO1248 sequence shown in FIG. 40 (SEQ IDNO:68) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 20, a transmembrane domain fromabout amino acid 90 to about amino acid 112 and potentialN-glycosylation sites from about amino acid 21 to about amino acid 24,from about amino acid 38 to about amino acid 41 and from about aminoacid 47 to about amino acid 50. Clone DNA60278-1530 has been depositedwith ATCC on Sep. 1, 1998 and is assigned ATCC deposit no. 203170.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 40 (SEQ ID NO:68), evidenced significant homology betweenthe PRO1248 amino acid sequence and the following Dayhoff sequences:AF026198_(—)5, CELR12C12_(—)5, PN0563, S64541_(—)1, PN0564, P_R44881 andXLU78189_(—)1.

Example 24 Isolation of cDNA Clones Encoding Human PRO1316

The extracellular domain (ECD) which includes the signal sequence, ifany, of publicly available databases known to contain secreted sequenceswere used to search various publicly available EST (Expressed SequencedTag) databases (GenBank, Merck/Wash. U). The search was performed usingthe computer program BLAST or BLAST2 [Altschul et al., Methods inEnzymology 266: 460-480 (1996)] as a comparison of the ECD proteinsequences to a 6 frame translation of the EST sequences. Thosecomparisons resulting in a BLAST score of 70 (or in some cases 90) orgreater that did not did not encode known proteins were clustered andassembled into consensus DNA sequences with the program “phrap” (PhilGreen, University of Washington, Seattle, Wash.).

The above search resulted in the identification of the EST, designatedW55979 which showed homology with the secreted protein Dkk-1. The clonecorresponding to EST W55979 (clone NbHH19W) was purchased fromMerck/Washington University and the cDNA insert was obtained andsequenced in its entirety.

The nucleic acid sequence corresponding to the full length PRO1316(designated DNA60608-1577) encoded by the purchased clone, is shown inFIG. 41 (SEQ ID NO:69). DNA60608-1577 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 211-213, and a stop codon at nucleotide positions 988-990(FIG. 42; SEQ ID NO:70). The predicted polypeptide precursor is 259amino acids long. Additional regions of significant interest include thenucleotide residues encoding the signal peptide (211-283), anN-glycosylation site (364-366), and the Zn(2)-Cys(6) binuclear clusterdomain (505-655). Clone DNA60608-1577 has been deposited with ATCC andis assigned ATCC deposit no. 203126. The full-length PRO1316 proteinshown in FIG. 42 has an estimated molecular weight of about 28,447daltons and a pI of about 9.48.

Based on a BLAST and FastA sequence alignment analysis (using the ALIGNcomputer program) of the full-length sequence, PRO1316 shows significantamino acid sequence identity to the dickkopf family of proteins.Additionally, DNA60608 has shown homology to AF030433_(—)1, LFE4_CHICK,COL_RABIT, YQ16_CAEEL, ITB6_HUMAN, CONO_LYMST, S41033, D63483_(—)1,D86864_(—)1 and AB001978_(—)1.

Example 25 Isolation of cDNA Clones Encoding Human PRO1197

An initial DNA sequence, referred to herein as DNA56267, was identifiedusing a yeast screen, in a human SK-Lu-1 adenocarcinoma cDNA librarythat preferentially represents the 5′ ends of the primary cDNA clones.DNA56267 was used to synthesize oligonucleotides for use as probes toisolate a clone of the full-length coding sequence for PRO1197 from ahuman breast carcinoma cDNA library.

-   -   SEQ ID NO:73: 5′AATTCATGGCAAATATTTCCCTTCCC3′ (forward);    -   SEQ ID NO:74: 5′TGGTAAACTGGCCCAAACTCGG3′ (reverse); and    -   SEQ ID NO:75:        5′TTAAAGTCATCCGTCCTTGGCTCAGGATGGAGAGCTTGCACCACCAAA3′ (probe).

The full length DNA60611-1524 clone shown in FIG. 43 contained a singleopen reading frame with an apparent translational initiation site atnucleotide positions 311-313 and ending at the stop codon found atnucleotide positions 1400-1402 (FIG. 43; SEQ ID NO:71). The predictedpolypeptide precursor (FIG. 44, SEQ ID NO:72) is 363 amino acids long.The signal peptide is at about amino acids 1-24 of SEQ ID NO:72. PRO1197has a calculated molecular weight of approximately 38,825 daltons and anestimated pI of approximately 9.88. Clone DNA60611-1524 has beendeposited with ATCC and is assigned ATCC deposit no. 203175.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 44 (SEQ ID NO:72), revealed sequence identity between thePRO1197 amino acid sequence and the following Dayhoff sequences(information from database incorporated herein): Y144_HUMAN, I47141 (agastric mucin, mucins are described in Ann. NY Acad. Sci., 140(2):804-834 (1967), AMYH_YEAST, CELK06A9_(—)3, CELZK783_(—)1, HKR1_YEAST,AB003521_(—)1, D87895_(—)1, S61993 and YM96_YEAST.

Example 26 Isolation of cDNA Clones Encoding Human PRO1293

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 115204. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56522.

In light of the sequence homology between the DNA56522 sequence and anEST contained within the Incyte EST clone no. 2966119, the Incyte ESTclone no. 2966119 was purchased and the cDNA insert was obtained andsequenced. The sequence of this cDNA insert is shown in FIG. 45 and isherein designated as DNA60618-1557.

Clone DNA60618-1557 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 37-39 andending at the stop codon at nucleotide positions 1060-1062 (FIG. 45).The predicted polypeptide precursor is 341 amino acids long (FIG. 46).The full-length PRO1293 protein shown in FIG. 46 has an estimatedmolecular weight of about 38,070 daltons and a pI of about 6.88.Analysis of the full-length PRO1293 sequence shown in FIG. 46 (SEQ IDNO:77) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 19, a transmembrane domain fromabout amino acid 237 to about amino acid 262, a potentialN-glycosylation site from about amino acid 205 to about amino acid 208,a cell attachment sequence from about amino acid 151 to about amino acid152 and an amino acid sequence block having homology tocoproporphyrinogen III oxidase proteins from about amino acid 115 toabout amino acid 140. Clone DNA60618-1557 has been deposited with ATCCon Sep. 29, 1998 and is assigned ATCC deposit no. 203292.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 46 (SEQ ID NO:77), evidenced significant homology betweenthe PRO1293 amino acid sequence and the following Dayhoff sequences:HSVCD54_(—)1, A33_HUMAN, AF009220_(—)1, HSU82279_(—)1, AF004230_(—)1,P_R13272, AF004231_(—)1, AF043644_(—)1, S44125 and HSIGGHC85_(—)1.

Example 27 Isolation of cDNA Clones Encoding Human PRO1380

A cDNA sequence isolated in the amylase screen described in Example 2above is herein designated DNA45776. Based on the DNA45776 sequence,oligonucleotide probes were generated and used to screen a human retinalibrary prepared as described in paragraph 1 of Example 2 above. Thecloning vector was pRK5B (pRK5B is a precursor of pRK5D that does notcontain the SfiI site; see, Holmes et al., Science, 253: 1278-1280(1991)), and the cDNA size cut was less than 2800 bp.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (45776.f1) 5′-TTTTGCGGTCACCATTGTCTGC-3′ (SEQ ID    NO:80) and-   reverse PCR primer (45776.r1) 5′-CGTAGGTGACACAGAAGCCCAGG-3′ (SEQ ID    NO:81).    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the DNA45776 sequence which had the following    nucleotide sequence:-   hybridization probe (45776.p1)    5′-TACGGCATGACCGGCTCCTTTCCTATGAGGAACTCCCAGGCACTGATAT-3′ (SEQ ID    NO:82).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1380 gene using the probe oligonucleotideand one of the PCR primers.

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 36-38, and a stop signal at nucleotide positions 1461-1463(FIG. 47; SEQ ID NO:78). The predicted polypeptide precursor is 470amino acids long has a calculated molecular weight of approximately51,715 daltons and an estimated pI of approximately 7.86. Additionalfeatures include transmembrane domains at about amino acids 50-74,105-127, 135-153, 163-183, 228-252, 305-330, and 448-472; potentialN-glycosylation sites at about amino acids 14-17 and 84-87; and adihydrofolate reductase signature at about amino acids 60-68.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 48 (SEQ ID NO:79), evidenced homology between the PRO1380amino acid sequence and the following Dayhoff sequences: HSU81375_(—)1,CEZK809_(—)6, CEK02E11_(—)1, AF034102_(—)1, JC4196, CEF36H2_(—)2,P_R92315, YAC2_YEAST, F1707_(—)13, and CEF44D12_(—)3.

Clone DNA60740-1615 was deposited with the ATCC on Nov. 3, 1998, and isassigned ATCC deposit no. 203456.

Example 28 Isolation of cDNA Clones Encoding Human PRO1265

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated EST Cluster No. 86995. This EST cluster sequencewas then compared to a variety of expressed sequence tag (EST) databaseswhich included public EST databases (e.g., GenBank) and a proprietaryEST DNA database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.)to identify existing homologies. The homology search was performed usingthe computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266: 460-480 (1996)). Those comparisons resulting in a BLASTscore of 70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into a consensus DNA sequence withthe program “phrap” (Phil Green, University of Washington, Seattle,Wash.). One or more of the ESTs used in the assembly was derived from acDNA library prepared from RNA isolated from inflamed human adenoidtissue. The consensus sequence obtained therefrom is herein designatedDNA55717.

In light of the sequence homology between the DNA55717 sequence and anEST sequence contained within Incyte EST no. 20965, EST clone no. 20965was purchased and the cDNA insert was obtained and sequenced. Thesequence of this cDNA insert is shown in FIG. 49 and is hereindesignated as DNA60764.

The full length clone shown in FIG. 49 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 79-81 and ending at the stop codon found at nucleotidepositions 1780-1782 (FIG. 49; SEQ ID NO:83). The predicted polypeptideprecursor (FIG. 50, SEQ ID NO:84) is 567 amino acids long. PRO1265 has acalculated molecular weight of approximately 62,881 daltons and anestimated pI of approximately 8.97. Additional features include a signalpeptide sequence at about amino acids 1-21; potential N-glycosylationsites at about amino acids 54-57, 134-137, 220-223, and 559-562; and aregion having amino acid sequence identity with D-amino acid oxidaseproteins at about amino acids 61-80.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 50 (SEQ ID NO:84), revealed significant sequence identitybetween the PRO1265 amino acid sequence and Dayhoff sequence no.MMU70429_(—)1. Sequence homology was also found to exist between thefull-length sequence shown in FIG. 50 (SEQ ID NO:84) and the followingadditional Dayhoff sequences: BC542A_(—)1, E69899, S76290, MTV014_(—)14,AOFB_HUMAN, ZMJ002204_(—)1, S45812_(—)1, DBRNAPD_(—)1, and CRT1_SOYBN.

Clone DNA60764-1533 was deposited with the ATCC on Nov. 10, 1998, and isassigned ATCC deposit no. 203452.

Example 29 Isolation of cDNA Clones Encoding Human PRO1250

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 56523. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Washington). The consensus sequence obtainedtherefrom is herein designated DNA56103.

In light of the sequence homology between the DNA56103 sequence and anEST sequence contained within the Incyte EST clone no.3371784, theIncyte EST clone no. 3371784 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 51 and is herein designated as DNA60775-1532.

Clone DNA60775-1532 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 74-76 andending at the stop codon at nucleotide positions 2291-2293 (FIG. 51).The predicted polypeptide precursor is 739 amino acids long (FIG. 52).The full-length PRO1250 protein shown in FIG. 52 has an estimatedmolecular weight of about 82,263 daltons and a pI of about 7.55.Analysis of the full-length PRO1250 sequence shown in FIG. 52 (SEQ IDNO:86) evidences the presence of the following: a type II transmembranedomain from about amino acid 61 to about amino acid 80, a putativeAMP-binding domain signature sequence from about amino acid 314 to aboutamino acid 325, and potential N-glycosylation sites from about aminoacid 102 to about amino acid 105, from about amino acid 588 to aboutamino acid 591 and from about amino acid 619 to about amino acid 622.Clone DNA60775-1532 has been deposited with ATCC on Sep. 1, 1998 and isassigned ATCC deposit no. 203173.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 52 (SEQ ID NO:86), evidenced significant homology betweenthe PRO1250 amino acid sequence and the following Dayhoff sequences:LCFB_HUMAN, S56508_(—)1, BNAMPBP2_(—)1, BNACS7_(—)1, CELT08B1_(—)6,CELC46F4_(—)2, AF008206_(—)6, CELR07C3_(—)11, LMU70253_(—)2 andAF008206_(—)7.

Example 30 Isolation of cDNA Clones Encoding Human PRO1475

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA45639. Based on the DNA45639 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1475.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (45639.f1) 5′-GATGGCAAAACGTGTGTTTGACACG-3′ (SEQ    ID NO:89)-   forward PCR primer (45639.f2) 5′-CCTCAACCAGGCCACGGGCCAC-3′ (SEQ ID    NO:90)-   reverse PCR primer (45639.r1) 5′-CCCAGGCAGAGATGCAGTACAGGC-3′ (SEQ ID    NO:91)-   reverse PCR primer (45639.r2) 5′-CCTCCAGTAGGTGGATGGATTGGCTC-3′ (SEQ    ID NO:92)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA45639 sequence which had the    following nucleotide sequence hybridization probe (45639.p1)-   5′-CTCACCTCATGAGGATGAGGCCATGGTGCTATTCCTCAACATGGTAG-3′ (SEQ ID NO:93)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1475 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal brain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1475 (designated herein as DNA61185-1646[FIG. 53, SEQ ID NO:87]; and the derived protein sequence for PRO1475.

The entire nucleotide sequence of DNA61185-1646 is shown in FIG. 53 (SEQID NO:87). Clone DNA61185-1646 contains a single open reading frame withan apparent translational initiation site at nucleotide positions130-132 and ending at the stop codon at nucleotide positions 2110-2112(FIG. 53). The predicted polypeptide precursor is 660 amino acids long(FIG. 54). The full-length PRO1475 protein shown in FIG. 54 has anestimated molecular weight of about 75,220 daltons and a pI of about6.76. Analysis of the full-length PRO1475 sequence shown in FIG. 54 (SEQID NO:88) evidences the presence of the following: a transmembranedomain from about amino acid 38 to about amino acid 55 and a homologousregion to mouse GNT1 from about amino acid 229 to about amino acid 660.Clone DNA61185-1646 has been deposited with ATCC on Nov. 17, 1998 and isassigned ATCC deposit no. 203464.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 54 (SEQ ID NO:88), evidenced significant homology betweenthe PRO1475 amino acid sequence and the following Dayhoff sequences:GNT1_MOUSE, CGU65792_(—)1, CGU65791_(—)1, P_R24781, CELF48E3_(—)1,G786_HUMAN, P_WO6547, GNT1_CAEEL, 219_HUMAN and EF07_MOUSE.

Example 31 Isolation of cDNA Clones Encoding Human PRO1377

An initial DNA sequence, referred to herein as DNA46892, was identifiedusing a yeast screen, in a human umbilical vein endothelial cell cDNAlibrary that preferentially represents the 5′ ends of the primary cDNAclones. Based on the DNA46892 sequence, the following oligonucleotideswere synthesized for use as probes to isolate a clone of the full-lengthcoding sequence for PRO1377 from a human fetal kidney cDNA library:GTTGTGGGTGAATAAAGGAGGGCAG (SEQ ID NO:96), CTGTGCTCATGTTCATGGACAACTG (SEQID NO:97), and GGATGATTTCATCTCCATTAGCCTGCTGTCTCTGGCTATGTTGGTGGGAT (SEQID NO:98).

The full length DNA61608-1606 clone shown in FIG. 55 contained a singleopen reading frame with an apparent translational initiation site atnucleotide positions 149-151 and ending at the stop codon found atnucleotide positions 1070-1072 (FIG. 55; SEQ ID NO:94). The predictedpolypeptide precursor (FIG. 56, SEQ ID NO:95) is 307 amino acids long.PRO1377 has a calculated molecular weight of approximately 32,251daltons and an estimated pI of approximately 6.62. Additional featuresinclude: a signal peptide at about amino acids 1-18; potentialN-glycosylation sites at about amino acids 29-32 and 241-244, andtransmembrane domains at about amino acids 37-56, 106-122, 211-230,240-260, and 288-304.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 56 (SEQ ID NO:95), revealed some homology between thePRO1377 amino acid sequence and the following Dayhoff sequences:CETOID3_(—)6, CET28F3_(—)4, CEF26D10_(—)3, S66962, ATX2_YEAST,CEH13N06_(—)8, S49959, YIC3_YEAST, G02273, and P W35557.

Clone DNA61608-1606 has been deposited with ATCC and is assigned ATCCdeposit no. 203239.

Example 32 Isolation of cDNA Clones Encoding Human PRO1326

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated Incyte Cluster No. 59366, also referred herein as“DNA10295”. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). One or more ofthe ESTs was derived from RNA isolated from tumor tissue removed fromthe penis of a male with squamous cell carcinoma. The consensus sequenceobtained therefrom is herein designated DNA56257.

In light of the sequence homology between the DNA56257 sequence and anEST sequence contained within Incyte EST no. 1450878, the EST clone1450878 was purchased and the cDNA insert was obtained and sequenced inits entirety. The sequence of this cDNA insert is shown in FIG. 57 andis herein designated as “DNA62808-1582”.

The full length clone shown in FIG. 57 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 112 to 114 and ending at the stop codon found at nucleotidepositions 1315 to 1317 (FIG. 57; SEQ ID NO:99). The predictedpolypeptide precursor (FIG. 58, SEQ ID NO:100) is 401 amino acids long.Other features of the PRO1326 protein include: a signal sequence atabout amino acids 1-29; a ribosomal protein S3Ae homologous region atabout amino acids 129-166; and potential N-glycosylation sites at aboutamino acids 109-112, 144-147 and 398-401. PRO1326 has a calculatedmolecular weight of approximately 45,333 daltons and an estimated pI ofapproximately 4.95. Clone DNA62808-1582 was deposited with the ATCC onOct. 20, 1998 and is assigned ATCC deposit no. 203358.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 58 (SEQ ID NO:100), revealed some homology between thePRO1326 amino acid sequence and the following Dayhoff sequences:AC004013_(—)1, HROMHCEMB_(—)1, CEF47A4_(—)2, A45592, MYSP_HUMAN,NFU43192_(—)1, ONGMBWMZ_(—)1, CELC25A11_(—)2, CELC25A11_(—)1, andA42184.

Example 33 Isolation of cDNA Clones Encoding Human PRO1249

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster no. 122605. This EST clustersequence was then compared to a variety of expressed sequence tag (EST)databases which included public EST databases (e.g., GenBank) and aproprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals, PaloAlto, Calif.) to identify existing homologies. The homology search wasperformed using the computer program BLAST or BLAST2 (Altshul et al.,Methods in Enzymology 266: 460-480 (1996)). Those comparisons resultingin a BLAST score of 70 (or in some cases 90) or greater that did notencode known proteins were clustered and assembled into a consensus DNAsequence with the program “phrap” (Phil Green, University of Washington,Seattle, Wash.). The consensus sequence obtained therefrom is hereindesignated DNA56060.

In light of the sequence homology between the DNA56060 sequence and anEST sequence contained within the Incyte EST clone no. 2630770, theIncyte EST clone no. 2630770 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 59 and is herein designated as DNA62809-1531.

Clone DNA62809-1531 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 3-5 andending at the stop codon at nucleotide positions 3270-3272 (FIG. 59).The predicted polypeptide precursor is 1089 amino acids long (FIG. 60).The full-length PRO1249 protein shown in FIG. 60 has an estimatedmolecular weight of about 118,699 daltons and a pI of about 8.49.Analysis of the full-length PRO1249 sequence shown in FIG. 60 (SEQ IDNO:102) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 16, transmembrane domains fromabout amino acid position 317 to about amino acid position 341, fromabout amino acid position 451 to about amino acid position 470, fromabout amino acid position 481 to about amino acid position 500, fromabout amino acid position 510 to about amino acid position 527, fromabout amino acid position 538 to about amino acid position 555, fromabout amino acid position 831 to about amino acid position 850, fromabout amino acid position 1016 to about amino acid position 1034 andfrom about amino acid position 1052 to about amino acid position 1070, aleucine zipper pattern sequence from about amino acid 843 to about aminoacid 864 and potential N-glycosylations sites from about amino acid 37to about amino acid 40 and from about amino acid 268 to about amino acid271. Clone DNA62809-1531 has been deposited with ATCC on Sep. 9, 1998and is assigned ATCC deposit no. 203237.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 60 (SEQ ID NO:102), evidenced significant homology betweenthe PRO1249 amino acid sequence and the following Dayhoff sequences:AC004472_(—)3, AB004539_(—)7, S64782, S62432. YJG2_YEAST,CELC27A12_(—)8, YKQ5_YEAST, AB009505_(—)3, SPBC24E9_(—)8 andAF060218_(—)4.

Example 34 Isolation of cDNA Clones Encoding Human PRO1315

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35925. Based on the DNA35925 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1315.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (35925.f1) 5′-CGCTGCTGCTGTTGCTCCTGG-3′ (SEQ ID    NO:105)-   forward PCR primer (35925.f2) 5′-CAGTGTGCCAGGACTTTG-3′ (SEQ ID    NO:106)-   forward PCR trimer (35925.f3) 5′-AGTCGCAGGCAGCGTTGG-3′ (SEQ ID    NO:107)-   reverse PCR primer (35925.r1) 5′-CTCCTCCGAGTCTGTGTGCTCCTGC-3′ (SEQ    ID NO:108)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA35925 sequence which had the    following nucleotide sequence-   hybridization probe (35925.p1)    5′-GGACGGGCAGTTCCCTGTGTCTCTGGTGGTTTGCCTAAACCTGCAAACATC-3′ (SEQ ID    NO:109)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1315 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human retina tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1315 (designated herein as DNA62815-1576[FIG. 61, SEQ ID NO:103]; and the derived protein sequence for PRO1315.

The entire nucleotide sequence of DNA62815-1576 is shown in FIG. 61 (SEQID NO:103). Clone DNA62815-1576 contains a single open reading framewith an apparent translational initiation site at nucleotide positions121-123 and ending at the stop codon at nucleotide positions 1447-1449(FIG. 61). The predicted polypeptide precursor is 442 amino acids long(FIG. 62). The full-length PRO1315 protein shown in FIG. 62 has anestimated molecular weight of about 49,932 daltons and a pI of about4.55. Analysis of the full-length PRO1315 sequence shown in FIG. 62 (SEQID NO:104) evidences the presence of the following: a signal peptidefrom about amino acid 1 to about amino acid 28, a transmembrane domainfrom about amino acid 140 to about amino acid 163 and potentialN-glycosylation sites from about amino acid 71 to about amino acid 74,from about amino acid 80 to about amino acid 83, from about amino acid89 to about amino acid 92, from about amino acid 204 to about amino acid207 and from about amino acid 423 to about amino acid 426. CloneDNA62815-1576 has been deposited with ATCC on Sep. 9, 1998 and isassigned ATCC deposit no. 203247.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 62 (SEQ ID NO:104), evidenced significant homology betweenthe PRO1315 amino acid sequence and the following Dayhoff sequences:MMU53696_(—)1, NVY08571_(—)2, B64560, STMSLPE_(—)1, P_R80508, P_W19258,A55817, GEN14043, AE000768_(—)7 and RNMUCASGP5_(—)1pSMC.

Example 35 Isolation of cDNA Clones Encoding Human PRO1599

Incyte EST no. 1491360 was identified as a sequence of interest usingthe techniques described in Example 1 above having a BLAST score of 70or greater that does not encode a known protein. The nucleotide sequenceof EST no. 1491360 and its complementary sequence is designated herein“DNA37192”. Based on the DNA37192 sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO1599.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: GACGTCTGCAACAGCTCCTGGAAG (37192.f1; SEQ ID    NO:112)-   reverse PCR primer: CGAGAAGGAAACGAGGCCGTGAG (37192.r1; SEQ ID    NO:113)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA37192 sequence which had the followingnucleotide sequence:

-   hybridization probe: TGACACTTACCATGCTCTGCACCCGCAGTGGGGACAGCCACAGA    (SEQ ID NO:114).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1599 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1599 (designated herein as DNA62845-1684[FIG. 63, SEQ ID NO:110]; and the derived protein sequence for PRO1599.

The entire coding sequence of PRO1599 is shown in FIG. 63 (SEQ IDNO:110). Clone DNA62845-1684 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 69-71and an apparent stop codon at nucleotide positions 918-920. Thepredicted polypeptide precursor is 283 amino acids long. The full-lengthPRO1599 protein shown in FIG. 64 has an estimated molecular weight ofabout 30,350 daltons and a pI of about 9.66. Additional features ofPRO1599 include: a signal peptide at about amino acids 1-30; potentialN-glycosylation sites at about amino acids 129-132 and 189-192; apotential cAMP and cGMP-dependent protein kinase phosphorylation site atabout amino acids 263-266; potential N-myristoylation sites at aboutamino acids 28-33, 55-60, 174-179, and 236-241; a potential amidationsite at about amino acids 144-147; and a serine protease, trypsinfamily, histidine active site at about amino acids 70-75.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 64 (SEQ ID NO:111), revealed significant homology betweenthe PRO1599 amino acid sequence and the following Dayhoff sequence:CFAD_PIG. Homology was also found between the PRO1599 amino acidssequence and the following additional Dayhoff sequences. CFAD_HUMAN;P_R05421; P_R55757; P_R05772; GRAM_HUMAN; MUSLMET_(—)1; P_P80335;P_R55758; A42048_(—)1; and P_WO5383.

Clone DNA62845-1684 was deposited with the ATCC on Oct. 20, 1998 and isassigned ATCC deposit no. 203361.

Example 36 Isolation of cDNA Clones Encoding Human PRO1430

A DNA sequence designated herein as DNA49433 was obtained as describedin Example 1 above. Merck EST no. T49469, which was identified as beingan EST of interest from the assembly, was purchased and the cDNA insertwas obtained and sequenced in entirety.

DNA sequencing of the clone as described above gave the full-length DNAsequence for PRO1430, which is designated herein as “DNA64842-1632” (SEQID NO:115), and the derived protein sequence for PRO1430 (SEQ IDNO:116). Clone DNA64842-1632 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 82-84,and an apparent stop codon at nucleotide positions 1075-1077. Thefull-length PRO1430 protein shown in FIG. 66 has an estimated molecularweight of about 35,932 daltons and a pI of about 8.45. The predictedpolypeptide precursor is 331 amino acids long. Additional featuresinclude a signal peptide at about amino acids 1-17; a potentialN-glycosylation site at about amino acids 171-174, and regions ofhomology with short chain alcohol dehydrogenase family proteins at aboutamino acids 29-51, 116-126, 180-217, and 222-230.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 66 (SEQ ID NO:116), revealed significant homology betweenthe PRO1430 amino acid sequence and Dayhoff sequence no. P_WO3198.Homology was also found between the PRO1430 amino acid sequence and thefollowing Dayhoff sequences: MTV030_(—)10, MTV037_(—)2, A40116_(—)1,S42651, CEC15H11_(—)6, SPCC736_(—)13, SCU43704_(—)1, S19842, OXIR_STRAT,and OXIR_STRLI.

Clone DNA64842-1632 has been deposited with ATCC and is assigned ATCCdeposit no. 203278.

Example 37 Isolation of cDNA Clones Encoding Human PRO1374

A consensus DNA sequence encoding PRO1374 was assembled relative toother EST sequences using phrap as described in Example 1 above. Thisconsensus sequence is designated herein “DNA47357”. Based on theDNA47357 consensus sequence, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence of interest,and 2) for use as probes to isolate a clone of the full-length codingsequence for PRO1374.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′CGGGACAGGAGACCCAGAAAGGG3′ (SEQ ID NO:119) and;-   reverse PCR primer 5′GGCCAAGTGATCCAAGGCATCTTC3′ (SEQ ID NO:120).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA47357 sequence which had the followingnucleotide sequence:

-   hybridization probe    5′CTGCGGGACCTGACTAGATTCTACGACAAGGTACTTTCTTTGCATGGGG 3′ (SEQ ID    NO:121).

In order to screen several libraries for a source of a full-lengthclone. DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1374 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from a human adenocarcinoma cell line.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1374 and the derived protein sequencefor PRO1374.

The entire coding sequence of PRO1374 is shown in FIG. 67 (SEQ IDNO:117). Clone DNA64849-1604 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 20-22and an apparent stop codon at nucleotide positions 1653-1655 of SEQ IDNO:117. The predicted polypeptide precursor is 544 amino acids long. Theapproximate locations of the signal peptide, N-glycosylation sites,leucine zipper patterns, and ribonucleotide reductase small subunitsignature are indicated in FIG. 68. Clone DNA64849-1604 has beendeposited with the ATCC and is assigned ATCC deposit no. 203468. Thefull-length PRO1374 protein shown in FIG. 68 has an estimated molecularweight of about 61,126 daltons and a pI of about 6.4.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 68 (SEQ ID NO:118), revealed sequence identity between thePRO1374 amino acid sequence and the following Dayhoff sequences:CEF35G2_(—)4, P_W37046, S44204, CET28D6_(—)1, CET20B3_(—)6,CELC14E2_(—)3, CUAL_CHICK, ATM7J2_(—)3, S74997 and HIVH5994R8_(—)1.

Example 38 Isolation of cDNA Clones Encoding Human PRO1311

A cDNA sequence isolated in the amylase screen described in Example 2above is herein designated DNA37721. The DNA37721 sequence was thencompared to a variety of expressed sequence tag (EST) databases whichincluded public EST databases (e.g., GenBank) and proprietary EST DNAdatabases (LIFESEQ™, Incyte Pharmaceuticals, Palo Alto, Calif.:Genentech, South San Franscisco, Calif.) to identify existinghomologies. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into consensus DNA sequences with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). The consensussequence obtained therefrom is herein designated “DNA48616”. Based onthe DNA48616 sequence, oligonucleotide probes were generated and used toscreen a human aortic endothelial cell library prepared as described inparagraph 1 of Example 2 above. The cloning vector was pRKSB (pRK5B is aprecursor of pRK5D that does not contain the SfiI site; see, Holmes etal., Science, 253: 1278-1280 (1991)), and the cDNA size cut was lessthan 2800 bp.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (48616.f1) 5′-ATCATCTATTCCACCGTGTTCTGGC-3′ (SEQ    ID NO:124)-   reverse PCR primer (48616.r1) 5′-GACAGAGTGCTCCATGATGATGTCC-3′ (SEQ    ID NO:125)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the DNA48616 sequence which had the following    nucleotide sequence:-   hybridization probe (48616.p1)    5′-CCTGTCTGTGGGCATCTATGCAGAGGTTGAGCGGCAGAAATATAAAACCC-3′ (SEQ ID    NO:126)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1311 gene using the probe oligonucleotideand one of the PCR primers.

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 195-197, and a stop signal at nucleotide positions 1077-1079(FIG. 69; SEQ ID NO:122). The predicted polypeptide precursor is 294amino acids long has a calculated molecular weight of approximately33,211 daltons and an estimated pI of approximately 5.35 Additionalfeatures include: a signal sequence at about amino acids 1-44; possibletransmembrane domains at about amino acids 22-42, 57-85, 94-116, and230-257; potential N-glycosylation sites at about amino acids 118-121,1899-192, and 230-233; potential tyrosine kinase phosphorylation sitesat about amino acids 3-11 and 129-136; potential N-myristoylation sitesat about amino acids 80-85, 109-114, 180-185, 218-223, 248-253, 276-281,285-290, and 287-292; and a cell attachment sequence at about aminoacids 3-5.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 70 (SEQ ID NO:123), evidenced some homology between thePRO1311 amino acid sequence and the following Dayhoff sequences:AF065389_(—)1, AF053455_(—)1, CD63_HUMAN, A15_HUMAN, AF043906_(—)1,C151_HUMAN, AF053453_(—)1, AF054838_(—)1, P_R91446, and CD82_HUMAN.

Clone DNA64863-1573 was deposited with the ATCC on Sep. 9, 1998, and isassigned ATCC deposit no. 203251.

Example 39 Isolation of cDNA Clones Encoding Human PRO1357

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 69537. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56034.

In light of the sequence homology between the DNA56034 sequence and anEST sequence contained within the Incyte EST clone no. 936239, theIncyte EST clone no. 936239 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 71 and is herein designated as DNA64881-1602.

Clone DNA64881-1602 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 74-76 andending at the stop codon at nucleotide positions 1526-1528 (FIG. 71).The predicted polypeptide precursor is 484 amino acids long (FIG. 72).The full-length PRO1357 protein shown in FIG. 72 has an estimatedmolecular weight of about 52,468 daltons and a pI of about 7.14.Analysis of the full-length PRO1357 sequence shown in FIG. 72 (SEQ IDNO:128) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 21, potential N-glycosylationsites from about amino acid 48 to about amino acid 51, from about aminoacid 264 to about amino acid 267 and from about amino acid 401 to aboutamino acid 404, a glycosaminoglycan attachment site from about aminoacid 412 to about amino acid 415 and an amino acid sequence block havinghomology to the LBP/BPI/CETP family of proteins from about amino acid407 to about amino acid 457. Clone DNA64881-1602 has been deposited withATCC on Sep. 9, 1998 and is assigned ATCC deposit no. 203240.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 72 (SEQ ID NO:128), evidenced significant homology betweenthe PRO1357 amino acid sequence and the following Dayhoff sequences:MMU46068_(—)1, S17447, MMU1_(—)1, BPI_RABIT, P_W16808, P_R21844,PSP_MOUSE, HSLBPEX1_(—)1 and BTU79413_(—)1.

Example 40 Isolation of cDNA Clones Encoding Human PRO1244

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated cluster no. 7874. This EST cluster sequence wasthen compared to a variety of expressed sequence tag (EST) databaseswhich included public EST databases (e.g., GenBank) and a proprietaryEST DNA databases (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.;Genentech, South San Francisco, Calif.) to identify existing homologies.One or more of the ESTs was derived from a library constructed fromtissue of the corpus cavernosum. The homology search was performed usingthe computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266: 460-480 (1996)). Those comparisons resulting in a BLASTscore of 70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into a consensus DNA sequence withthe program “phrap” (Phil Green, University of Washington, Seattle,Wash.). The consensus sequence obtained therefrom is herein designatedDNA56011”.

In light of the sequence homology between the DNA56011 sequence and anEST sequence contained within Incyte EST No. 3202349, the EST clone no.3202349 was purchased and the cDNA insert was obtained and sequenced.The sequence of this cDNA insert is shown in FIG. 73 (SEQ ID NO:129) andis herein designated “DNA64883-1526”.

The full length clone shown in FIG. 73 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 9-11 and ending at the stop codon found at nucleotidepositions 1014-1016 (FIG. 73; SEQ ID NO:129). The predicted polypeptideprecursor (FIG. 74, SEQ ID NO:130) is 335 amino acids long. PRO1244 hasa calculated molecular weight of approximately 38,037 daltons and anestimated pI of approximately 9.87. Other features include a signalpeptide at about amino acids 1-29; transmembrane domains at about aminoacids 183-205, 217-237, 271-287, and 301-321; potential N-glycosylationsites at about amino acids 71-74, and 215-218; and a cell attachmentsequence at about amino acids 150-152.

An analysis of (he Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 74 (SEQ ID NO:130), revealed homology between the PRO1244amino acid sequence and the following Dayhoff sequences: AF008554_(—)1,P_(—)485334, G02297, HUMN33S11_(—)1, HUMN33S10_(—)1, YO13_CAEEL,GEN13255, S49758, E70107, and ERP5_MEDSA.

Clone DNA64883-1526 was deposited with the ATCC on Sep. 9, 1998, and isassigned ATCC deposit no. 203253.

Example 41 Isolation of cDNA Clones Encoding Human PRO1246

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 56853. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 6: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56021.

In light of the sequence homology between the DNA56021 sequence and anEST sequence contained within the Incyte EST clone no. 2481345, theIncyte EST clone no. 2481345 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 75 and is herein designated as DNA64885-1529.

Clone DNA64885-1529 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 119-121and ending at the stop codon at nucleotide positions 1727-1729 (FIG.75). The predicted polypeptide precursor is 536 amino acids long (FIG.76). The full-length PRO1246 protein shown in FIG. 76 has an estimatedmolecular weight of about 61,450 daltons and a pI of about 9.17.Analysis of the full-length PRO1246 sequence shown in FIG. 76 (SEQ IDNO:132) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 15, potential N-glycosylationsites from about amino acid 108 to about amino acid 111, from aboutamino acid 166 to about amino acid 169, from about amino acid 193 toabout amino acid 196, from about amino acid 262 to about amino acid 265,from about amino acid 375 to about amino acid 378, from about amino acid413 to about amino acid 416 and from about amino acid 498 to about aminoacid 501 and amino acid sequence blocks having homology to sulfataseproteins from about amino acid 286 to about amino acid 315, from aboutamino acid 359 to about amino acid 369 and from about amino acid 78 toabout amino acid 97. Clone DNA64885-1529 has been deposited with ATCC onNov. 3, 1998 and is assigned ATCC deposit no. 203457.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 76 (SEQ ID NO:132), evidenced significant homology betweenthe PRO1246 amino acid sequence and the following Dayhoff sequences:P_R51355, CELK09C4_(—)1, BCU44852_(—)1, IDS_HUMAN, G65169, E64903,ARSA_HUMAN, GL6S_HUMAN, HSARSF_(—)1 and GEN12648.

Example 42 Isolation of cDNA Clones Encoding Human PRO1356

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 44725. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzmmology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56023.

In light of the sequence homology between the DNA56023 sequence and anEST sequence contained within the Incyte EST clone no.4071746, theIncyte EST clone no. 4071746 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 77 and is herein designated as DNA64886-1601.

Clone DNA64886-1601 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 122-124and ending at the stop codon at nucleotide positions 812-814 (FIG. 77).The predicted polypeptide precursor is 230 amino acids long (FIG. 78).The full-length PRO1356 protein shown in FIG. 78 has an estimatedmolecular weight of about 24,549 daltons and a pI of about 8.56.Analysis of the full-length PRO1356 sequence shown in FIG. 78 (SEQ IDNO:134) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 24, transmembrane domains fromabout amino acid 82 to about amino acid 102, from about amino acid 117to about amino acid 140 and from about amino acid 163 to about aminoacid 182, a potential N-glycosylation site from about amino acid 190 toabout amino acid 193 and an amino acid sequence block having homology tothe PMP-22/EMP/MP20 family of proteins from about amino acid 46 to aboutamino acid 59. Clone DNA64886-1601 has been deposited with ATCC on Sep.9, 1998 and is assigned ATCC deposit no. 203241.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 78 (SEQ ID NO:134), evidenced significant homology betweenthe PRO1356 amino acid sequence and the following Dayhoff sequences:AB00014_(—)1, AB000712_(—)1, A39484, AF000959_(—)1, AF035814_(—)1,HSU89916_(—)1, MMU19582_(—)1, P_R30059,HUAC004125_(—)1 and PM22_RAT.

Example 43 Isolation of cDNA Clones Encoding Human PRO1275

A novel secreted molecule, designated herein as DNA57700, was used toBLAST against Incyte's (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto,Calif.) proprietary database and Genbank's public database. Positiveclones were identified and used to generate assembly files by seqextprogram. The search was performed using the computer program BLAST orBLAST2 [Altschul et al., Methods in Enzymology, 266: 460-480 (1996)] asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Those comparisons resulting in a BLAST score of 70(or in some cases, 90) or greater that did not encode known proteinswere clustered and assembled into consensus DNA sequences with theprogram “phrap” (Phil Green, University of Washington, Seattle, Wash.).

A consensus DNA sequence was assembled relative to other EST sequencesusing repeated cycles of BLAST and phrap. This consensus sequence isdesignated herein “DNA59572”.

Based on the DNA59572 consensus sequence and its relation to sequencesidentified in the assembly, one of the clones (Incyte clone 2026581)including one of the sequences in the assembly was purchased andsequenced. Incyte clone 2026581 came from a library constructed of RNAfrom epidermal breast keratinocytes.

The entire coding sequence of PRO1275 is shown in FIG. 79 (SEQ IDNO:135). Clone DNA64888-1542 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 37-39and an apparent stop codon at nucleotide positions 394-396 of SEQ IDNO:135. The predicted polypeptide precursor is 119 amino acids long. Thesignal peptide is at about amino acids 1-25 of SEQ ID NO:136. CloneDNA64888-1542 has been deposited with ATCC and is assigned ATCC depositno. 203249. The full-length PRO1275 protein shown in FIG. 79 has anestimated molecular weight of about 13,248 daltons and a pI of about7.78.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 80 (SEQ ID NO:136), revealed sequence identity between thePRO1275 amino acid sequence and the following Dayhoff sequences(information from database incorporated herein): B48151 (Mst98Cb),D86424_(—)1 (high-sulfur keratin protein), P_R79964 (connective tissuegrowth factor), CHRD_RAT (chordin), MT_DREPO (metallothionein),PL05_PLETR (plectoxins), P_R25156 (Ig antigen), S73732_(—)1 (VLDP),AF025440_(—)1 (OIP4) and P_R32757 (IGF-II).

Example 44 Isolation of cDNA Clones Encoding Human PRO1274

A novel secreted molecule, designated herein as DNA57700, was used toblast against Incyte's (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto,Calif.) proprietary database and Genbank's public database. Positiveclones were identified and used to generate assembly files by seqextprogram. The search was performed using the computer program BLAST orBLAST2 [Altschul et al., Methods in Enzymology, 266: 460-480 (1996)] asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Those comparisons resulting in a BLAST score of 70(or in some cases, 90) or greater that did not encode known proteinswere clustered and assembled into consensus DNA sequences with theprogram “phrap” (Phil Green, University of Washington, Seattle, Wash.).

A consensus DNA sequence was assembled relative to other EST sequencesusing repeated cycles of BLAST and phrap. This consensus sequence isdesignated herein “DNA59573”.

Based on the DNA59573 consensus sequence and its relation to sequencesidentified in the assembly, one of the clones (Incyte clone 2623992)including one of the sequences in the assembly was purchased andsequenced. Incyte clone 2623992 came from a library constructed of RNAfrom epidermal breast keratinocytes.

The entire coding sequence of PRO1274 is shown in FIG. 81 (SEQ IDNO:137). Clone DNA64889-1541 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 24-26,and an apparent stop codon at nucleotide positions 354-356 of SEQ IDNO:137. The predicted polypeptide precursor is 110 amino acids long. Thesignal peptide is at about 1-24 of SEQ ID NO:138. Conserved regions inthe insulin family of proteins and an N-glycosylation site are indicatedin FIG. 82. Clone DNA64889-1541 has been deposited with ATCC and isassigned ATCC deposit no. 203250. The full-length PRO1274 protein shownin FIG. 82 has an estimated molecular weight of about 12,363 daltons anda pI of about 8.31.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 82 (SEQ ID NO:138), revealed sequence identity between thePRO1274 amino acid sequence and the following Dayhoff sequences(information from database incorporated herein): CEW05B2_(—)9,AF016922_(—)1 (insulin-like growth factor 1), B48151, A53640,BTIGF2REC_(—)1 (insulin-like growth factor 2), HSNFIGEN12_(—)1,TXA3_RADMA (neurotoxin 3), CXM1_CONGE, P_P61301, TXA4_RADMA (neurotoxin4).

Example 45 Isolation of cDNA Clones Encoding Human PRO1412

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated Incyte Cluster No. 101368, also referred herein as“DNA10643”. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology, 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). One or more ofthe ESTs was derived from RNA isolated from fibroblasts of the prostatestroma removed from a male fetus. The consensus sequence obtainedtherefrom is herein designated “DNA58754”.

In light of the sequence homology between the DNA58754 sequence and anEST sequence contained within EST no. 3597385, the EST clone 3597385 waspurchased and the cDNA insert was obtained and sequenced in itsentirety. The sequence of this cDNA insert is shown in FIG. 83 and isherein designated as “DNA64897-1628”.

The full length clone shown in FIG. 83 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 142 to 144 and ending at the stop codon found at nucleotidepositions 1075 to 1077 (FIG. 83; SEQ ID NO:139). The predictedpolypeptide precursor (FIG. 84, SEQ ID NO:140) is 311 amino acids long.Other features of the PRO1412 protein include: a signal sequence atabout amino acids 1-28; a transmembrane domain at about amino acids190-216; potential N-glycosylation sites at about amino acids 49-52,91-94, 108-111, 128-131, 135-138 and 190-193; a tyrosine kinasephosphorylation site at about amino acids 62-69; and alysosome-associated membrane glycoprotein duplicated domain at aboutamino acids 183-224. PRO1412 has a calculated molecular weight ofapproximately 33,908 daltons and an estimated pI of approximately 6.87.Clone DNA64897-1628 was deposited with the ATCC on Sep. 15, 1998, and isassigned ATCC deposit no. 203216.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 84 (SEQ ID NO:140), revealed some homology between thePRO1412 amino acid sequence and the following Dayhoff sequences: I50116,AF035963_(—)1, NCA2_RAT, I61783, P_WO7682, MMHC135G15_(—)3, S21461,MMIGL2_(—)1, ONHIGMV9A_(—)1 and MMU70448_(—)1.

Example 46 Isolation of cDNA Clones Encoding Human PRO1557

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST sequence from the Genentech database,designated “DNA58763. This EST sequence was then compared to a varietyof expressed sequence tag (EST) databases, which included the ESTdatabases listed above, to identify existing homologies. The homologysearch was performed using the computer program BLAST or BLAST2 (Altshulet al., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtained from theassembly is herein designated “DNA58763”.

In light of the sequence homology between the DNA58763 sequence and anEST sequence contained within the EST no. 2267403, EST no. 2267403 waspurchased and the cDNA insert was obtained and sequenced. The sequenceof this cDNA insert is shown in FIG. 85 and is herein designated asDNA64902-1667.

The full length clone shown in FIG. 85 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 287 to 289 and ending at the stop codon found at nucleotidepositions 1640 to 1642 (FIG. 85; SEQ ID NO:141). The predictedpolypeptide precursor (FIG. 86, SEQ ID NO:142) is 451 amino acids long.PRO1557 has a calculated molecular weight of approximately 49,675daltons and an estimated pI of approximately 7.15. Additional featuresinclude: a signal sequence at about amino acids 1-25; a potentialN-glycosylation site at about amino acids 114-117; a potential cAMP andcGMP-dependent protein kinase phosphorylation site at about amino acids388-41; potential N-myristoylation sites at about amino acids 54-49,66-71, 146-151, and 367-372; potential amidation sites at about aminoacids 36-39 and 205-208; and an ATP/GTP-binding site motif A (P-loop) atabout amino acids 151-258.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 86 (SEQ ID NO:142), revealed significant homology betweenthe PRO1557 amino acid sequence and Dayhoff sequence AF034606_(—)1.Homology was also found between the PRO1557 amino acid sequence and thefollowing Dayhoff sequences: P_W31559, AF031230_(—)1, SOG_DROME,CA11_MOUSE, P_R41320, CHRD_RAT, P_W40288, NEL_CHICK, and HSMUC5B_(—)1.

Clone DNA64902-1667 was deposited with the ATCC on Oct. 6, 1998, and isassigned ATCC deposit no. 203317.

Example 47 Isolation of cDNA Clones Encoding Human PRO1286

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated EST Cluster No. 86809. This EST cluster sequencewas then compared to a variety of expressed sequence tag (EST) databaseswhich included public EST databases (e.g., GenBank) and a proprietaryEST DNA database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.)to identify existing homologies. The homology search was performed usingthe computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266: 460-480 (1996)). Those comparisons resulting in a BLASTscore of 70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into a consensus DNA sequence withthe program “phrap” (Phil Green, University of Washington, Seattle,Wash.). ESTs in the assembly included those identified from tumors, celllines, or diseased tissue. One or more of the ESTs was obtained from acDNA library constructed from RNA isolated from diseased colon tissue.The consensus sequence obtained therefrom is herein designated DNA58822.

In light of the sequence homology between the DNA58822 sequence and anEST sequence contained within EST no. 1695434, EST clone no. 1695434 waspurchased and the cDNA insert was obtained and sequenced. The sequenceof this cDNA insert is shown in FIG. 87 and is herein designatedDNA64903-1553 (SEQ ID NO:143).

The full length clone shown in FIG. 87 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 93-95 and ending at the stop codon found at nucleotidepositions 372-374 (FIG. 87; SEQ ID NO:143). The predicted polypeptideprecursor (FIG. 88, SEQ ID NO:144) is 93 amino acids long, with a signalsequence at about amino acids 1-18. PRO1286 has a calculated molecularweight of approximately 10,111 daltons and an estimated pI ofapproximately 9.70.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 88 (SEQ ID NO:144), revealed some homology between thePRO1286 amino acid sequence and the following Dayhoff sequences:SR5C_ARATH, CELC17H12_(—)11, MCPD_ENTAE, JQ2283, INVO_LEMCA, P_R07309,ADEVBCAGN_(—)4, AF020947_(—)1, CELT23H2_(—)1, and MDH_STRAR.

Clone DNA64903-1553 was deposited with the ATCC on Sep. 15, 1998 and isassigned ATCC deposit no. 203223.

Example 48 Isolation of cDNA Clones Encoding Human PRO1294

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 10559. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (LIFESEQ®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA57203.

In light of the sequence homology between the DNA57203 sequence and anEST sequence contained within the Incyte EST clone no. 3037763, theIncyte EST clone no. 3037763 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 89 and is herein designated as DNA64905-1558.

Clone DNA64905-1558 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 110-112and ending at the stop codon at nucleotide positions 1328-1330 (FIG.89). The predicted polypeptide precursor is 406 amino acids long (FIG.90). The full-length PRO1294 protein shown in FIG. 90 has an estimatedmolecular weight of about 46,038 daltons and a pI of about 6.50.Analysis of the full-length PRO1294 sequence shown in FIG. 90 (SEQ IDNO:146) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 21 and potential N-glycosylationsites from about amino acid 177 to about amino acid 180 and from aboutamino acid 248 to about amino acid 251. Clone DNA64905-1558 has beendeposited with ATCC on Sep. 15, 1998 and is assigned ATCC deposit no.203233.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 90 (SEQ ID NO:146), evidenced significant homology betweenthe PRO1294 amino acid sequence and the following Dayhoff sequences:I73636, AF028740_(—)1, AB006686S3_(—)1, P_R98225, RNU78105_(—)1,CELC48E7_(—)4, CEF11C3_(—)3, SCP1_MESAU, TPM3_HUMAN and CELKO5B2_(—)3.

Example 49 Isolation of cDNA Clones Encoding Human PRO1347

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “DNA47373”. Based on the DNA47373 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1347.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′GCGTGGTCCACCTCTACAGGGACG3′ (SEQ ID NO:149); and-   reverse PCR primer 5′GGAACTGACCCAGTGCTGACACC3′ (SEQ ID NO:150).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA47373 sequence which had the followingnucleotide sequence:

-   hybridization probe    5′GCAGATGCCACAGTATCAAGGCAGGACAAAACTGGTGAAGGATTC3′ (SEQ ID NO:151).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1347 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human small intestine.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1347 and the derived protein sequencefor PRO1347.

The entire coding sequence of PRO1347 is shown in FIG. 91 (SEQ IDNO:147). Clone DNA64950-1590 contains a single open reading frame withan apparent translational initiation site at nucleotide positions183-185, and an apparent stop codon at nucleotide positions 1683-1685 ofSEQ ID NO:147. The predicted polypeptide precursor is 500 amino acidslong. The signal peptide is at about amino acids 1-17 and thetransmembrane domain is at about 239-255 of SEQ ID NO:148. CloneDNA64950-1590 has been deposited with ATCC and is assigned ATCC depositno. 203224. The full-length PRO1347 protein shown in FIG. 92 has anestimated molecular weight of about 56,748 daltons and a pI of about8.5.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 92 (SEQ ID NO:148), revealed sequence identity between thePRO1347 amino acid sequence and the following Dayhoff sequences (dataincorporated herein): BUTY_HUMAN, AF033107_(—)1, HSU90142_(—)1,HSU90144_(—)1, HSB73_(—)1, HS111M5_(—)2, RO52_HUMAN, AF018080_(—)1,HSAJ03147_(—)4, and MOG_MOUSE.

Example 50 Isolation of cDNA Clones Encoding Human PRO1305

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA38103. Based on the DNA38103 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1305.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (38103.f1) 5′-AACTGCTCTGTGGTTGGAAGCCTG-3′ (SEQ ID    NO:154)-   reverse PCR primer (38103.r1) 5′-CAGTCACATGGCTGACAGACCCAC-3′ (SEQ ID    NO:155)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA38103 sequence which had the    following nucleotide sequence-   hybridization probe (38103.p1)    5′-AGGTTATCAGGGGCTTCACTGTGAAACCTGCAAAGAGG-3′ (SEQ ID NO:156)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1305 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1305 (designated herein as DNA64952-1568[FIG. 93, SEQ ID NO:152]; and the derived protein sequence for PRO1305.

The entire nucleotide sequence of DNA64952-1568 is shown in FIG. 93 (SEQID NO:152). Clone DNA64952-1568 contains a single open reading framewith an apparent translational initiation site at nucleotide positions126-128 and ending at the stop codon at nucleotide positions 900-902(FIG. 93). The predicted polypeptide precursor is 258 amino acids long(FIG. 94). The full-length PRO1305 protein shown in FIG. 94 has anestimated molecular weight of about 25,716 daltons and a pI of about8.13. Analysis of the full-length PRO1305 sequence shown in FIG. 94 (SEQID NO:153) evidences the presence of the following: a signal peptidefrom about amino acid 1 to about amino acid 25, potentialN-glycosylation sites from about amino acid 30 to about amino acid 33,from about amino acid 172 to about amino acid 175, from about amino acid195 to about amino acid 198, from about amino acid 208 to about aminoacid 211 and from about amino acid 235 to about amino acid 238 and anEGF-like domain cysteine pattern signature sequence from about aminoacid 214 to about amino acid 225. Clone DNA64952-1568 has been depositedwith ATCC on Sep. 15, 1998 and is assigned ATCC deposit no. 203222.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 94 (SEQ ID NO:153), evidenced significant homology betweenthe PRO1305 amino acid sequence and the following Dayhoff sequences:CET22A3_(—)7, LMA2_MOUSE, AF055580_(—)1, AF016903_(—)1, LMB2_MOUSE,P_R71730, LMB3_MOUSE, LMG1_HUMAN. LMG1_DROME and LMA5_MOUSE. As such,the PRO1305 polypeptide does show homology to laminin and may be alaminin homolog.

Example 51 Isolation of cDNA Clones Encoding Human PRO1273

An expressed sequence tag (EST) DNA database (LIFESEQ®, IncytePharmaceuticals, Palo Alto, Calif.) was searched and an EST wasidentified. This sequence was blasted against public databases andIncyte's database. The search was performed using the computer programBLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266: 460-480(1996)] as a comparison of the extracellular domain (ECD) proteinsequences to a 6 frame translation of the EST sequences. Thosecomparisons resulting in a BLAST score of 70 (or in some cases, 90) orgreater that did not encode known proteins were clustered and assembledinto consensus DNA sequences with the program “phrap” (Phil Green,University of Washington, Seattle, Wash.).

A consensus DNA sequence was assembled relative to other EST sequencesusing repeated cycles of BLAST and phrap. This consensus sequence isdesignated herein “DNA60747”. Based on the DNA60747 consensus sequenceand its relation to a sequence within the assembly of aligned sequences,Incyte clone 3541105 was purchased and sequenced in full. This Incyteclone came from a library constructed of RNA isolated from seminalvesicle tissue.

The entire coding sequence of PRO1273 is shown in FIG. 95 (SEQ IDNO:157). Clone DNA65402-1540 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 26-28and an apparent stop codon at nucleotide positions 515-517 of SEQ IDNO:157. The predicted polypeptide precursor is 163 amino acids long. Thesignal peptide is at about amino acids 1-20 and the conserved region inlipocalins is at about amino acids 25-36 of SEQ ID NO:158. CloneDNA65402-1540 has been deposited with ATCC and is assigned ATCC depositno. 203252. The full-length PRO1273 protein shown in FIG. 96 has anestimated molecular weight of about 18,045 daltons and a pI of about4.87.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 96 (SEQ ID NO:158), revealed sequence identity between thePRO1273 amino acid sequence and the following Dayhoff sequences(information from database incorporated herein): PGHD_FELCA(prostaglandin-h2 d-isomerase precursor), S57748 (prostaglandin Dsynthetase precursor), LIPO_BUFMA (lipocalin precursor), S52354,QSP_CHICK, ECP19_(—)1, LACB_CAPHI, OLFA_RANPI, D87752_(—)1, andLACB_BOVIN.

Example 52 Isolation of cDNA Clones Encoding Human PRO1302

A consensus DNA sequence encoding PRO1302 was assembled relative toother EST sequences using repeated cycles of phrap as described inExample 1 above. This consensus sequence is designated herein“DNA28742”. Based on the DNA28742 consensus sequence, the assembly fromwhich the consensus sequence was derived and other information anddiscoveries provided herein, the Incyte clone 3344926 (from a diseasedspleen tissue library) was purchased and sequenced in full. Sequencingprovided the full-length DNA sequence for PRO1302 and the derivedprotein sequence for PRO1302.

The entire coding sequence of PRO1302 is shown in FIG. 97 (SEQ IDNO:159). Clone DNA65403-1565 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 43-45and an apparent stop codon at nucleotide positions 1432-1435 of SEQ IDNO:159. The predicted polypeptide precursor is 463 amino acids long. Thesignal peptide is at about amino acids 1-15 and the transmembranesequence is at about amino acids 351-370 of SEQ ID NO:160. CloneDNA65403-1565 has been deposited with the ATCC and is assigned ATCCdeposit no. 203230. The full-length PRO1302 protein shown in FIG. 98 hasan estimated molecular weight of about 50,082 daltons and a pI of about7.3.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 98 (SEQ ID NO:160), revealed sequence identity between thePRO1302 amino acid sequence and the following Dayhoff Sequences (dataincorporated herein): D86358_(—)1, D86359_(—)1, S71403_(—)1, MAG_HUMAN,JH0593, MMSIAL2_(—)1, C22A_HUMAN, PGBM_HUMAN, PGBM_HUMAN, LACH_DROME,and KMLS_HUMAN.

Example 53 Isolation of cDNA Clones Encoding Human PRO1283

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28753. Based on the DNA28753 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1283.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (28753.f1) 5′-GGAGATGAAGACCCTGTTCCTG-3′ (SEQ ID    NO:163)-   forward PCR primer (28753.f11) 5′-GGAGATGAAGACCCTGTTCCTGGGTG-3′ (SEQ    ID NO:164)-   reverse PCR primer (28753.r1) 5′-GTCCTCCGGAAAGTCCTTATC-3′ (SEQ ID    NO:165)-   reverse PCR primer (28753.r11) 5′-GCCTAGTGTTCGGGAACGCAGCTTC-3′ (SEQ    ID NO:166)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA28753 sequence which had the    following nucleotide sequence-   hybridization probe (28753.p1)    5′-CAGGGACCTGGTACGTGAAGGCCATGGTGGTCGATAAGGACTTTCCGGAG-3′ (SEQ ID    NO:167)-   hybridization probe (28753.p11)    5′-CTGTCCTTCACCCTGGAGGAGGAGGATATCACAGGGACCTGGTAC-3′ (SEQ ID NO:168)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1283 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human breast tumor tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1283 (designated herein as DNA65404-1551[FIG. 99, SEQ ID NO:161]; and the derived protein sequence for PRO1283.

The entire nucleotide sequence of DNA65404-1551 is shown in FIG. 99 (SEQID NO:161). Clone DNA65404-1551 contains a single open reading framewith an apparent translational initiation site at nucleotide positions45-47 and ending at the stop codon at nucleotide positions 555-557 (FIG.99). The predicted polypeptide precursor is 170 amino acids long (FIG.100). The full-length PRO1283 protein shown in FIG. 100 has an estimatedmolecular weight of about 19,457 daltons and a pI of about 9.10.Analysis of the full-length PRO1283 sequence shown in FIG. 100 (SEQ IDNO:162) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 17. Clone DNA65404-1551 has beendeposited with ATCC on Sep. 9, 1998 and is assigned ATCC deposit no.203244.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 100 (SEQ ID NO:162), evidenced significant homologybetween the PRO1283 amino acid sequence and the following Dayhoffsequences: A40464, VEGP_HUMAN, ALL1_CANFA, LALP_TRIVU, S51803,XELPDS_(—)1, LIPO_BUFMA, S52354, QSP_CHICK and ERBP_RAT.

Example 54 Isolation of cDNA Clones Encoding Human PRO1279

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30856. Based on the DNA30856 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1279.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (30856.f1) 5′-GGCTGCGGGACTGGAAGTCATCGGG-3′ (SEQ    ID NO:171)-   forward PCR primer (30856.f11) 5′-CTCCAGGCCATGAGGATTCTGCAG-3′ (SEQ    ID NO:172)-   forward PCR primer (30856.f12) 5′-CCTCTGGTCTGTAACCAG-3′ (SEQ ID    NO:173)-   reverse PCR primer (30856.r1) 5′-TCTGTGATGTTGCCGGGGTAGGCG-3′ (SEQ ID    NO:174)-   reverse PCR primer (30856.r11) 5′-CGTGTAGACACCAGGCTTTCGGGTG-3′ (SEQ    ID NO:175)-   reverse PCR primer (30856.r12) 5′-CCCTTGATGATCCTGGTC-3′ (SEQ ID    NO:176)    Additionally, synthetic oligonucleotide hybridization probes were    constructed from the consensus DNA30856 sequence which had the    following nucleotide sequences-   hybridization probe (30856.p1)    5′-AGGCCATGAGGATTCTGCAGTTAATCCTGCTTGCTCTGGCAACAGGGCTT-3′ (SEQ ID    NO:177)-   hybridization probe (30856.p11)    5′-GAGAGACCAGGATCATCAAGGGGTTCGAGTGCAAGCCTCACTC-3′ (SEQ ID NO:178)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1279 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human lung tumor tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1279 (designated herein as DNA65405-1547[FIG. 101, SEQ ID NO:169]; and the derived protein sequence for PRO1279.

The entire nucleotide sequence of DNA65405-1547 is shown in FIG. 101(SEQ ID NO:169). Clone DNA65405-1547 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 106-108 and ending at the stop codon at nucleotide positions856-858 (FIG. 101). The predicted polypeptide precursor is 250 aminoacids long (FIG. 102). The full-length PRO1279 protein shown in FIG. 102has an estimated molecular weight of about 27,466 daltons and a pI ofabout 8.87. Analysis of the full-length PRO1279 sequence shown in FIG.102 (SEQ ID NO:170) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 18, a serineprotease, trypsin family, histidine active site from about amino acid 58to about amino acid 63, potential N-glycosylation sites from about aminoacid 99 to about amino acid 102, from about amino acid 165 to aboutamino acid 168, from about amino acid 181 to about amino acid 184 andfrom about amino acid 210 to about amino acid 213, a glycosaminoglycanattachment site from about amino acid 145 to about amino acid 148, aminoacid sequence blocks present in kringle domain proteins from about aminoacid 197 to about amino acid 209 and from about amino acid 47 to aboutamino acid 64, amino acid sequence blocks having homology to serineprotease, trypsin family, histidine proteins from about amino acid 199to about amino acid 209, from about amino acid 47 to about amino acid 63and from about amino acid 220 to about amino acid 243 and amino acidsequence blocks having homology to apple domain proteins from aboutamino acid 222 to about amino acid 249 and from about amino acid 189 toabout amino acid 222. Clone DNA65405-1547 has been deposited with ATCCon Nov. 17, 1998 and is assigned ATCC deposit no. 203476.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 102 (SEQ ID NO:170), evidenced significant homologybetween the PRO1279 amino acid sequence and the following Dayhoffsequences: I56559, S55066, KLK7_RAT, KLK1_RAT, KLKB_RAT, KLK3_MOUSE,KLK8_RAT, AF013988_(—)1, D78203_(—)1 and HSU62801_(—)1.

Additionally, DNA65405-1547 was obtained by purchasing the Incyte ESTclone no. 2723646 and sequencing the insert of that clone, therebygiving the DNA65405-1547 sequence shown in FIG. 101 (SEQ ID NO:169).

Example 55 Isolation of cDNA Clones Encoding Human PRO1304

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35745. Based on the DNA35745 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1304.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (35745.f1) 5′-GTGTTCTGCTGGAGCCGATGCC-3′ (SEQ ID    NO:181)-   forward PCR primer (35745.f2) 5′-GACATGGACAATGACAGG-3′ (SEQ ID    NO:182)-   forward PCR primer (35745.f3) 5′-CCTTTCAGGATGTAGGAG-3′ (SEQ ID    NO:183)-   forward PCR primer (35745.f4) 5′-GATGTCTGCCACCCCAAG-3′ (SEQ ID    NO:184)-   reverse PCR primer (35745.r1) 5′-GCATCCTGATATGACTTGTCACGTGGC-3′ (SEQ    ID NO:185)-   reverse PCR primer (35745.r2) 5′-TACAAGAGGGAAGAGGAGTTGCAC-3′ (SEQ ID    NO:186)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA35745 sequence which had the    following nucleotide sequence-   hybridization probe (35745.p1)    5′-GCCCATTATGACGGCTACCTGGCTAAAGACGGCTCGAAATTCTACTGCAGCC-3′ (SEQ ID    NO:187)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1304 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human ovary tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1304 (designated herein as DNA65406-1567[FIG. 103, SEQ ID NO:179]; and the derived protein sequence for PRO1304.

The entire nucleotide sequence of DNA65406-1567 is shown in FIG. 103(SEQ ID NO:179). Clone DNA65406-1567 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 23-25 and ending at the stop codon at nucleotide positions689-691 (FIG. 103). The predicted polypeptide precursor is 222 aminoacids long (FIG. 104). The full-length PRO1304 protein shown in FIG. 104has an estimated molecular weight of about 25,794 daltons and a pI ofabout 6.24. Analysis of the full-length PRO1304 sequence shown in FIG.104 (SEQ ID NO:180) evidences the presence of the following: anendoplasmic reticulum targeting sequence from about amino acid 219 toabout amino acid 222, a potential N-glycosylation site from about aminoacid 45 to about amino acid 48, FKBP-type peptidyl-prolyl cis-transisomerase homology blocks from about amino acid 87 to about amino acid123 and from about amino acid 129 to about amino acid 142 and EF-handcalcium binding domain protein homology blocks from about amino acid 202to about amino acid 214 and from about amino acid 195 to about aminoacid 214. Clone DNA65406-1567 has been deposited with ATCC on Sep. 15,1998 and is assigned ATCC deposit no. 203219.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 104 (SEQ ID NO:180), evidenced significant homologybetween the PRO1304 amino acid sequence and the following Dayhoffsequences: AF040252_(—)1, P_R28980, S71238, CELC05C8_(—)1,VFU52045_(—)1, S75144, FKB3_BOVIN, CELC50F2_(—)6, CELB0511_(—)12 andP_R41781.

The DNA65406-1567 sequence was also obtained by isolating and sequencingthe insert of Incyte EST clone no. 2813577.

Example 56 Isolation of cDNA Clones Encoding Human PRO1317

Using the technique described in Example 1 above, Incyte EST no. 33598was identified as a sequence of interest having a BLAST score of 70 orgreater that did not encode a known protein. The sequence of Incyte ESTno. 33598 is designated herein as “DNA36958”. Based on the DNA36958sequence, oligonucleotides can be synthesized: 1) to identify by PCR acDNA library that contains the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO1317.

The following are suitable PCR primers (forward and reverse) that can besynthesized based on the DNA36958 sequence:

-   forward PCR primer: AGGGACCATTGCTTCTTCCAGGCC (36958.f1; SEQ ID    NO:190)-   reverse PCR primer: CGTTACATGTCTCCAAGGGGAATG (36958.r1; SEQ ID    NO:191)

Additionally, a synthetic oligonucleotide hybridization probe can beconstructed from the consensus DNA36958 sequence having the followingnucleotide sequence:

-   hybridization probe:    CCTGTGCTAAGTGCCCCCCAAATGCTTCCTGTGTCAATAACACTCACTGC (36958.p1; SEQ ID    NO:192)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries is screened by PCR amplification with thePCR primer pair identified above. A positive library is then used toisolate clones encoding the PRO1317 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librariescan be isolated from tissue containing the sequence of interest, forexample from peripheral blood, particularly blood taken from a patienthaving a high leukocyte count (e.g hypereosinophilia).

The full-length DNA sequence for PRO1317, designated herein asDNA65408-1578 (FIG. 105; SEQ ID NO:188) was obtained by purchasingIncyte EST no. 335958, obtaining the cDNA insert, and sequencing it inits entirety. Incyte clone no. 335958 originated from a libraryconstructed using RNA isolated from peripheral blood cells apheresedfrom a male patient afflicted with hypereosinophilia.

The entire coding sequence of PRO1317 is shown in FIG. 105 (SEQ IDNO:188). Clone DNA65408-1578 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 6-8and an apparent stop codon at nucleotide positions 228-230. Thepredicted polypeptide precursor is 74 amino acids long. The full-lengthPRO1317 protein shown in FIG. 106 has an estimated molecular weight ofabout 7,831 daltons and a pI of about 9.08. Additional features include:a signal peptide at about amino acids 1-18, potential N-glycosylationsites at about amino acids 34-37 and 39-42, and a microbodies C-terminaltargeting signal at amino acids 72-74.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 106 (SEQ ID NO:189), revealed significant homology betweenthe PRO1317 amino acid sequence and the Dayhoff sequence designatedCD97_HUMAN. Additionally, some homology was found between the PRO1317amino acid sequence and the following Dayhoff sequences: GEN12618,CELZK783_(—)1, G156_PARPR, GIAVSPE_(—)1, AF040387_(—)1, S78059, I50617,XLSEK1_(—)1, and NEL2_RAT.

Clone DNA65408-1578 was deposited with the ATCC on Sep. 15, 1998, and isassigned ATCC deposit no. 203217.

Example 57 Isolation of cDNA Clones Encoding Human PRO1303

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “DNA47347”. Based on the DNA47347 consensus sequenceand its homology to an Incyte EST within the assembly from whichDNA47347 was derived, Incyte clone 1430305 (from an ileum tissuelibrary) was purchased and sequenced in full. The sequence encodingPRO1303 was thereby identified.

The entire coding sequence of PRO1303 is shown in FIG. 107 (SEQ IDNO:193). Clone DNA65409-1566 contains a single open reading frame withan apparent translational initiation site at nucleotide positions121-123 and an apparent stop codon at nucleotide positions 865-867. Thepredicted polypeptide precursor is 248 amino acids long. The signalpeptide is at about amino acids 1-17 of SEQ ID NO:194. The locations ofN-glycosylation sites, active and conserved regions and domains arefurther indicated in FIG. 194. Clone DNA65409-1566 has been depositedwith ATCC and is assigned ATCC deposit no. 203232. The full-lengthPRO1303 protein shown in FIG. 108 has an estimated molecular weight ofabout 26,734 daltons and a pI of about 7.9.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 108 (SEQ ID NO:194), revealed sequence identity betweenthe PRO1303 amino acid sequence and the following Dayhoff sequences(data incorporated herein): AB009849_(—)1, P_W08475, AF024605_(—)1,A42048_(—)1, TRY3_RAT, MMAE00066414, TRY1_RAT, MMAE000663_(—)4,MMAE000665_(—)2, and MMAE00066412.

Example 58 Isolation of cDNA Clones Encoding Human PRO1306

Using the method described in Example 1 above, Incyte EST No. 2449282,also referred to herein as DNA5918, was identified as a sequence ofinterest having a BLAST score of 70 or greater that did not encode aknown protein. From the DNA5918 sequence, a consensus sequence wasassembled using BLAST and the program “phrap” (Phil Green, University ofWashington, Seattle, Wash.). This consensus sequence is designatedherein as “DNA47399”. Based on the DNA47399 consensus sequence,oligonucleotides can be synthesized: 1) to identify by PCR a cDNAlibrary that contains the sequence of interest, and 2) for use as probesto isolate a clone of the full-length coding sequence for PRO1306.

The entire coding sequence of PRO1306 shown in FIG. 109 (SEQ ID NO:195),was obtained by purchasing Incyte EST no. 2449282, obtaining the cDNAinsert and sequencing it in its entirety. Clone DNA65410-1569 contains asingle open reading frame with an apparent translational initiation siteat nucleotide positions 106-108 and an apparent stop codon at nucleotidepositions 556-558. The predicted polypeptide precursor is 150 aminoacids long. The full-length PRO1306 protein shown in FIG. 110 has anestimated molecular weight of about 17,068 daltons, a pI of about 7.29,and a potential N-glycosylation site at about amino acids 131-134.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 110 (SEQ ID NO:196), revealed significant homology betweenthe PRO1306 amino acid sequence and Dayhoff sequence AIF1_HUMAN.Homology was also shown between the PRO1306 amino acid sequence and thefollowing Dayhoff sequences: JC4902, BAR1_RAT, AF020281_(—)1,HSU95213_(—)1, TCH3_ARATH, LEY14765_(—)1, CATR_NAEGR, S35185, andAF065247_(—)1.

Clone DNA65410-1569, was deposited with the ATCC on Sep. 15, 1998 and isassigned ATCC deposit no. 203231.

Example 59 Isolation of cDNA clones Encoding Human PRO1336

An EST sequence was identified and entered into a proprietary Genentechdatabase. The EST was blasted against various EST databases. The ESTdatabases included public EST databases (e.g., GenBank), and aproprietary EST database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto,Calif.), and proprietary ESTs from Genentech. The search was performedusing the computer program BLAST or BLAST2 [Altschul et al., Methods inEnzymology, 266: 460-480 (1996)] as a comparison of the ECD proteinsequences to a 6 frame translation of the EST sequences. Thosecomparisons resulting in a BLAST score of 70 (or in some cases, 90) orgreater that did not encode known proteins were clustered and assembledinto consensus DNA sequences with the program “phrap” (Phil Green,University of Washington, Seattle, Wash.).

A consensus DNA sequence encoding PRO1336 was assembled relative toother aligned EST sequences (forming an assembly) using phrap. Thisconsensus sequence is designated herein “DNA43319”. Based on theDNA43319 consensus sequence, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence of interest,and 2) for use as probes to isolate a clone of the full-length codingsequence for PRO1336.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′ATGGAGATTCCTGCCAACTTGCCG3′ (SEQ ID NO:199); and-   reverse PCR primer 5′TTGTTGGCATTGAGGAGGAGCAGC3′. (SEQ ID NO:200).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA43319 sequence which had the followingnucleotide sequence:

-   hybridization probe    5′GAGGGCATCGTCGAAATACGCCTAGAACAGAACTCCATCAAAGCCATCCC3′ (SEQ ID    NO:201).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1336 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal lung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1336 (designated herein as DNA65423-1595[FIGS. 111A-B, SEQ ID NO:198]; and the derived protein sequence forPRO1336.

The entire coding sequence of PRO1336 is shown in FIGS. 111A-B (SEQ IDNO:198). Clone DNA65423-1595 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 83-85and an apparent stop codon at nucleotide positions 4652-4654 of SEQ IDNO:198. The predicted polypeptide precursor is 1523 amino acids long.The approximate locations of the signal peptide (amino acids 1-27),aspartic acid and asparagine hydroxylation sites, EGF-like domaincystein pattern signature regions, a leucine zipper pattern region, aregion conserved in immunoglobulins and major histocompatibilitycomplexes, and N-glycosylation sites are indicated in FIG. 112. CloneDNA65423-1595 has been deposited with the ATCC and is assigned ATCCdeposit no. 203227. The full-length PRO1336 protein shown in FIG. 112has an estimated molecular weight of about 167,715 daltons and a pI ofabout 8.06.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 112 (SEQ ID NO:198), revealed sequence identity betweenthe PRO1336 amino acid sequence and the following Dayhoff sequences(data incorporated herein): SLIT_DROME, CEF40E10_(—)1, LCU58977_(—)1,AF029779_(—)1, FBP1_STRPU, NOTC_XENLA, AC004663_(—)1, XELXDEL_(—)1,P_WO5835 and HSU77720_(—)1.

Example 60 Isolation of cDNA Clones Encoding Human PRO1278

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “Consen5230”. In addition, the Consen5230 consensussequence was extended using repeated cycles of BLAST and phrap to extendthe consensus sequence as far as possible using the sources of ESTsequences discussed above. The extended consensus sequence is designatedherein as “DNA44801”. Based on the DNA44801 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1278.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primers: GCAGGCTTTGAGGATGAAGGCTGC (44801.f1; SEQ ID    NO:204) and CTCATTGGCTGCCTGGTCACAGGC (44801.r2; SEQ ID NO:205)-   reverse PCR primers: CCAGTCGGACAGGTCTCTCCCCTC (44801.r1; SEQ ID    NO:206) and TCAGTGACCAAGGCTGAGCAGGCG (44801.r2; SEQ ID NO:207)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA44801 sequence which had the followingnucleotide sequence:

-   hybridization probe: CTACACTCGTTGCAAACTGGCAAAAATATTCTCGAGGGCTGGCCTGG    (44801.p1; SEQ ID NO:208)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1278 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human testis.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1278 (designated herein as DNA66304-1546[FIG. 113, SEQ ID NO:202]; and the derived protein sequence for PRO1278.

The entire coding sequence of PRO1278 is shown in FIG. 113 (SEQ IDNO:202). Clone DNA66304-1546 contains a single open reading frame withan apparent translational initiation site at nucleotide positions141-143 and an apparent stop codon at nucleotide positions 585-587. Thepredicted polypeptide precursor is 148 amino acids long. The full-lengthPRO1278 protein shown in FIG. 114 has an estimated molecular weight ofabout 16,623 daltons and a pI of about 8.47. Additional features includea signal peptide sequence at about amino acids 1-19; a potentialN-glycosylation site at about amino acids 58-61; analpha-lactalbumin/lysozyme C signature at about amino acids 94-112; andhomolgy with alpha-lactalbumin/lysozyme C at about amino acids 35-59,67-59 and 112-133.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 114 (SEQ ID NO:203), revealed significant homology betweenthe PRO1278 amino acid sequence and the following Dayhoff sequences:LYC1_ANAPL, LYC3_ANAPL, and LYC_HUMAN.

Clone DNA66304-1546 was deposited with the ATCC on Oct. 6, 1998, and isassigned ATCC deposit no. 203321.

Example 61 Isolation of cDNA Clones Encoding Human PRO1298

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from an Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs was derived from a diseased prostatetissue library. The homology search was performed using the computerprogram BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (orin some cases 90) or greater that did not encode known proteins wereclustered and assembled into a consensus DNA sequence with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.). Theconsensus sequence obtained therefrom is herein designated DNA56389.

In light of the sequence homology between the DNA56389 sequence and anEST sequence contained within an Incyte EST within the assembly fromwith the consensus sequence was derived, Incyte clone 3355717 waspurchased and the cDNA insert was obtained and sequenced. The sequenceof this cDNA insert is shown in FIG. 115 and is herein designated asDNA66511-1563.

The full length clone shown in FIG. 115 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 94-96 and ending at the stop codon found at nucleotidepositions 1063-1065 (FIG. 115; SEQ ID NO:209). The predicted polypeptideprecursor (FIG. 116, SEQ ID NO:210) is 323 amino acids long. The signalpeptide is at about amino acids 1-15 of SEQ ID NO:210. PRO1298 has acalculated molecular weight of approximately 37,017 daltons and anestimated pI of approximately 8.83. Clone DNA66511-1563 was depositedwith the ATCC on Sep. 15, 1998 and is assigned ATCC deposit no. 203228.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 116 (SEQ ID NO:210), revealed sequence identity betweenthe PRO1298 amino acid sequence and the following Dayhoff sequences(data incorporated herein): ALG2_YEAST, CAPM_STAAU, C69098, C69255,SUS2_MAIZE, A69143, S74778, AB009527_(—)13, AF050103_(—)2 andBBA224769_(—)1.

Example 62 Isolation of cDNA Clones Encoding Human PRO1301

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated Incyte Cluster No. 93492, also referred herein as“DNA10591”. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). One or more ofthe ESTs was derived from a cDNA library constructed from RNA isolatedfrom lung tissue removed from a male with adenocarcinoma. The consensussequence obtained therefrom is herein designated “DNA57725”.

In light of the sequence homology between the DNA57725 sequence and anEST sequence contained within the EST no. 3395984, the EST clone 3395984was purchased and the cDNA insert was obtained and sequenced in itsentirety. The sequence of this cDNA insert is shown in FIG. 117 and isherein designated as “DNA66512-1564”.

The full length clone shown in FIG. 117 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 43 to 45 and ending at the stop codon found at nucleotidepositions 1429 to 1431 (FIG. 117; SEQ ID NO:211). The predictedpolypeptide precursor (FIG. 118, SEQ ID NO:212) is 462 amino acids long.Other features of the PRO1301 protein include: a signal sequence atabout amino acids 1-18; a transmembrane domain at about amino acids271-290; a cytochrome P450 homologous region at about amino acids134-462; and potential N-glycosylation sites at about amino acids 94-97,217-220, and 246-249. PRO1301 has a calculated molecular weight ofapproximately 52,432 daltons and an estimated pI of approximately 6.14.Clone DNA66512-1564 was deposited with the ATCC on Sep. 15, 1998 and isassigned ATCC deposit no. 203218.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 118 (SEQ ID NO:212), revealed some homology between thePRO1301 amino acid sequence and the following Dayhoff sequences:PSU29243_(—)1, A69975, ATAC00448418, D78607_(—)1, CEB0331_(—)1,HUMCYTIIIA_(—)1, AF014800_(—)1, CELT13C5_(—)4, CELC45H4_(—)14, andCEC54E10_(—)1.

Example 63 Isolation of cDNA Clones Encoding Human PRO1268

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated EST No. 8879. This EST cluster sequence was thencompared to a variety of expressed sequence tag (EST) databases whichincluded public EST databases (e.g., GenBank) and a proprietary EST DNAdatabase (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.) toidentify existing homologies. The homology search was performed usingthe computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266: 460-480 (1996)). Those comparisons resulting in a BLASTscore of 70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into a consensus DNA sequence withthe program “phrap” (Phil Green, University of Washington, Seattle,Wash.). One or more of the ESTs was derived from a cDNA libraryconstructed from human brain tumor tissue taken from a cerebral meningeslesion. The consensus sequence obtained therefrom is herein designatedDNA56258.

In light of the sequence homology between the DNA56258 sequence and anEST sequence contained within the Incyte EST no. 2944541, EST clone no.2944541 was purchased and the cDNA insert was obtained and sequenced.The sequence of this cDNA insert is shown in FIG. 119 and is hereindesignated as “DNA66519-1535”.

The full length clone shown in FIG. 119 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 89 to 91 and ending at the stop codon found at nucleotidepositions 509 to 511 (FIG. 119; SEQ ID NO:213). The predictedpolypeptide precursor (FIG. 120, SEQ ID NO:214) is 140 amino acids long.PRO1268 has a calculated molecular weight of approximately 15,503daltons and an estimated pI of approximately 6.44. Additional featuresinclude a type II transmembrane domain at about amino acids 12-28; typeI transmembrane domains at about amino acids 51-66 and 107-124; apotential N-glycosylation site at about amino acids 79-82, and a regionhaving homology with G-protein coupbled receptors at about amino acids59-99.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 120 (SEQ ID NO:214), revealed some homology between thePRO1268 amino acid sequence and Dayhoff sequence no. CEF39B2_(—)9.However, the percent sequence identity was determined to not besignificant.

Clone DNA66519-1535 was deposited with the ATCC on Sep. 15, 1998 and isassigned ATCC deposit no. 203236.

Example 64 Isolation of cDNA Clones Encoding Human PRO1269

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ™database, designated EST Cluster No. 101920. This EST cluster sequencewas then compared to a variety of expressed sequence tag (EST) databaseswhich included public EST databases (e.g., GenBank) and a proprietaryEST DNA database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.)to identify existing homologies. The homology search was performed usingthe computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266: 460-480 (1996)). Those comparisons resulting in a BLASTscore of 70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into a consensus DNA sequence withthe program “phrap” (Phil Green, University of Washington, Seattle,Wash.). The consensus sequence obtained therefrom is herein designatedDNA56509.

In light of the sequence homology between the DNA56509 sequence and anEST sequence contained within the EST no. 103157, EST clone no. 103157was purchased and the cDNA insert was obtained and sequenced. Thesequence of this cDNA insert is shown in FIG. 121 and is hereindesignated as DNA66520-1536.

The full length clone shown in FIG. 121 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 26-29 and ending at the stop codon found at nucleotidepositions 614-616 (FIG. 121; SEQ ID NO:215). The predicted polypeptideprecursor (FIG. 122, SEQ ID NO:216) is 196 amino acids long, with asignal peptide located at about amino acids 1-20. There is a potentialN-glycosylation site at about amino acids 112-115. PRO1269 has acalculated molecular weight of approximately 21,731 daltons and anestimated pI of approximately 8.97.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 122 (SEQ ID NO:216), revealed significant homology betweenthe PRO1269 amino acid sequence and the amino acid sequence of Dayhoffsequence no. P_W23722. In addition, sequence homology was found betweenthe PRO1269 amino acid sequences and the amino acid sequences of thefollowing Dayhoff sequences: MMTAG7_(—)1, MTV026_(—)16, NAAA_BPT3,S75616_(—)1, and NCP_PIG.

Clone DNA66520-1536 was deposited with the ATCC on Sep. 15, 1998, and isassigned ATCC deposit no. 203226.

Example 65 Isolation of cDNA Clones Encoding Human PRO1327

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 173410. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (LIFESEQ®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56520.

In light of the sequence homology between the DNA56520 sequence and anEST sequence contained within the Incyte EST clone no. 3451760, theIncyte EST clone no. 3451760 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 123 and is herein designated as DNA66521-1583.

Clone DNA66521-1583 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 55-57 andending at the stop codon at nucleotide positions 811-813 (FIG. 123). Thepredicted polypeptide precursor is 252 amino acids long (FIG. 124). Thefull-length PRO1327 protein shown in FIG. 124 has an estimated molecularweight of about 28,127daltons and a pI of about 8.91. Analysis of thefull-length PRO1327 sequence shown in FIG. 124 (SEQ ID NO:218) evidencesthe presence of the following: a signal peptide from about amino acid 1to about amino acid 14, potential N-glycosylation sites from about aminoacid 62 to about amino acid 65, from about amino acid 127 to about aminoacid 130, from about amino acid 137 to about amino acid 140 and fromabout amino acid 143 to about amino acid 146 and a 2-oxo aciddehydrogenase acyltransferase homology block from about amino acid 61 toabout amino acid 71. Clone DNA66521-1583 has been deposited with ATCC onSep. 15, 1998 and is assigned ATCC deposit no. 203225.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 124 (SEQ ID NO:218), evidenced significant homologybetween the PRO1327 amino acid sequence and the following Dayhoffsequences: NPH1_RAT, NPH2_MOUSE, OTU_DROME, D40750, BB61_RABIT,P_R23873, P_WO9643, CAGHMGPA_(—)1, HUMPRP11_(—)1 and S670958_(—)1.

Example 66 Isolation of cDNA Clones Encoding Human PRO1382

Using the method described in Example 1 above, Incyte EST no. 2719 wasidentified as a sequence of interest having a BLAST score of 70 orgreater that does not encode a known protein. The nucleotide sequence ofEST no. 2719 is designated herein “DNA42842”. Based on the DNA42842sequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO1382.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer ACGGCTCACCATGGGCTCCG (42842.f1; SEQ ID NO:221)-   reverse PCR primer AGGAAGAGGAGCCCTTGGAGTCCG (42842.r1; SEQ ID    NO:222)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA42842 sequence which had the followingnucleotide sequence:

-   hybridization probe CGTGCTGGAGGGCAAGTGTCTGGTGGTGTGCGACTCGAAC    (42842.p1; SEQ ID NO:223).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1382 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from a human breast carcinoma.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1382 (designated herein as DNA66526-1616[FIG. 125, SEQ ID NO:219]; and the derived protein sequence for PRO1382.

The entire coding sequence of PRO1382 is shown in FIG. 125 (SEQ IDNO:219). Clone DNA66526-1616 contains a single open reading frame withan apparent translational initiation site at nucleotide positions337-339 and an apparent stop codon at nucleotide positions 940-942. Thepredicted polypeptide precursor is 201 amino acids long. The full-lengthPRO1382 protein shown in FIG. 126 has an estimated molecular weight ofabout 21,808 daltons and a pI of about 9.04. Additional features includea signal peptide at about amino acids 1-27; potential N-glycosylationsites at about amino acids 29-32 and 88-91; and regions of homology withC1q proteins at about amino acids 92-126, 159-178, and 191-200.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 126 (SEQ ID NO:220), revealed significant homology betweenthe PRO1382 amino acid sequence Dayhoff sequence no. CERL_RAT. Homologywas also revealed between the PRO1382 amino acid sequence and thefollowing Dayhoff sequences: CERB_HUMAN, S76975_(—)1, A41752,HUMC1QB2_(—)1, A57131, CA1A_HUMAN, ACR3_MOUSE, and COLE_LEPMA.

Clone DNA66526-1616 has been deposited with ATCC and is assigned ATCCdeposit no. 203246.

Example 67 Isolation of cDNA Clones Encoding Human PRO1328

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 40671. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56749.

In light of the sequence homology between the DNA56749 sequence and anESt sequence contained within the Incyte EST clone no. 4111192, theIncyte EST clone no. 4111192 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 127 and is herein designated as DNA66658-1584.

Clone DNA66658-1584 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 9-11 andending at the stop codon at nucleotide positions 780-782 (FIG. 127). Thepredicted polypeptide precursor is 257 amino acids long (FIG. 128). Thefull-length PRO1328 protein shown in FIG. 128 has an estimated molecularweight of about 28,472 daltons and a pI of about 9.33. Analysis of thefull-length PRO1328 sequence shown in FIG. 128 (SEQ ID NO:225) evidencesthe presence of the following: a signal peptide from about amino acid 1to about amino acid 19, transmembrane domains from about amino acid 32to about amino acid 51, from about amino acid 119 to about amino acid138, from about amino acid 152 to about amino acid 169 and from aboutamino acid 216 to about amino acid 235, a glycosaminoglycan attachmentsite from about amino acid 120 to about amino acid 123 andsodium/nuerotransmitter symporter family protein homology block fromabout amino acid 31 to about amino acid 65. Clone DNA66658-1584 has beendeposited with ATCC on Sep. 15, 1998 and is assigned ATCC deposit no.203229.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 128 (SEQ ID NO:225), evidenced significant homologybetween the PRO1328 amino acid sequence and the following Dayhoffsequences: CEVF36H2L_(—)2, TIP2_TOBAC, AB009466_(—)16, ATU39485_(—)1,P_R60153, P_R77082, S73351, C69392, LEU95008_(—)1 and E64667.

Example 68 Isolation of cDNA Clones Encoding Human PRO1325

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 139524. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (Lifeseq®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56115.

In light of the sequence homology between the DNA56115 sequence and anEST sequence contained within the Incyte EST clone no. 3744079, theIncyte EST clone no. 3744079 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 129 and is herein designated as DNA66659-1593.

Clone DNA66659-1593 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 51-53 andending at the stop codon at nucleotide positions 2547-2549 (FIG. 129).The predicted polypeptide precursor is 832 amino acids long (FIG. 130).The full-length PRO1325 protein shown in FIG. 130 has an estimatedmolecular weight of about 94,454 daltons and a pI of about 6.94.Analysis of the full-length PRO1325 sequence shown in FIG. 130 (SEQ IDNO:227) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 18, transmembrane domains fromabout amino acid 292 to about amino acid 317, from about amino acid 451to about amino acid 470, from about amino acid 501 to about amino acid520, from about amino acid 607 to about amino acid 627 from about aminoacid 751 to about amino acid 770, a leucine zipper pattern sequence fromabout amino acid 497 to about amino acid 518 and potentialN-glycosylation sites from about amino acid 27 to about amino acid 30,from about amino acid 54 to about amino acid 57, from about amino acid60 to about amino acid 63, from about amino acid position 123 to aboutamino acid position 126, from about amino acid position 141 to aboutamino acid position 144, from about amino acid position 165 to aboutamino acid position 168, from about amino acid position 364 to aboutamino acid position 367, from about amino acid position 476 to aboutamino acid position 479, from about amino acid position 496 to aboutamino acid position 499, from about amino acid position 572 to aboutamino acid position 575, from about amino acid position 603 to aboutamino acid position 606 and from about amino acid position 699 to aboutamino acid position 702. Clone DNA66659-1593 has been deposited withATCC on Sep. 22, 1998 and is assigned ATCC deposit no. 203269.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 130 (SEQ ID NO:227), evidenced significant homologybetween the PRO1325 amino acid sequence and the following Dayhoffsequences: CELR04E5_(—)1, CELZK721_(—)5, CELC30E1_(—)5, CELC30E1_(—)6,CELC30E1_(—)2, CEY37H2C_(—)1, CELC30E1_(—)7, CELT07H8_(—)7 and E64006.

Example 69 Isolation of cDNA Clones Encoding Human PRO1340

Using the method set forth in Example 1 above, Incyte EST no. 878906 wasidentified as a sequence of interest having a BLAST score of 70 orgreater that does not encode a known protein. The nucleotide sequence ofEST no. 878906 is designated herein “DNA42809”. Based on the DNA42809sequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO1340.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer TCCAGGTGGACCCCACTTCAGG (42809.f1; SEQ ID NO:270)-   reverse PCR primer GGGAGGCTTATAGGCCCAATCTGG (42809.r1; SEQ ID    NO:271)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the DNA42809 sequence which had the followingnucleotide sequence:

-   hybridization probe    GGCTTCAGCAGCACGTGTGAAGTCGAAGTCGCAGTCACAGATATCAATGA (42809.p1; SEQ ID    NO:272)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1340 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1340 (designated herein as DNA66663-1598[FIG. 131, SEQ ID NO:228]; and the derived protein sequence for PRO1340.

The entire coding sequence of PRO1340 is shown in FIG. 131 (SEQ IDNO:228). Clone DNA66663-1598 contains a single open reading frame withan apparent translational initiation site at nucleotide positions128-130 and an apparent stop codon at nucleotide positions 2549-2551.The predicted polypeptide precursor is 807 amino acids long. Thefull-length PRO1340 protein shown in FIG. 132 has an estimated molecularweight of about 87,614 daltons and a pI of about 4.83. Additionalfeatures include: a signal peptide at about amino acids 1-18; atransmembrane domain at about amino acids 762-784; a cell attachmentsequence at about amino acids 492-494; potential N-glycosylation sitesat about amino acids 517-520, 602-605 and 700-703; and cadherinextracellular repeat domains at about amino acids 307-351, 324-348,67-103, 97-141 and 114-138.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 132 (SEQ ID NO:229), revealed significant homology betweenthe PRO1340 amino acid sequence and Dayhoff sequence no. 146536.Homology was also revealed between the PRO1340 amino acid sequence andthe following Dayhoff sequences: S55396, RATPDRPT_(—)1, CADD_CHICK,CAD1_CHICK, CADB_CHICK, I50180, CAD4_CHICK, G02878, and DSC1_MOUSE.

Clone DNA66663-1598 has been deposited with ATCC and is assigned ATCCdeposit no. 203268.

Example 70 Isolation of cDNA Clones Encoding Human PRO1339

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “DNA40652”. Within the consensus sequence assembly wasIncyte EST 2479394. Based on the consensus sequence and otherdiscoveries and information provided herein, the clone including IncyteEST 2479394 was purchased and sequenced in full. Sequencing provided thenucleic acid sequence shown in FIG. 133 which includes the sequenceencoding PRO1339.

Clone DNA66669-1597 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 9-11 andan apparent stop codon at nucleotide positions 1272-1274 of SEQ IDNO:233. The predicted polypeptide precursor is 421 amino acids long. Thesignal peptide is at about amino acids 1-16 of SEQ ID NO:234. The regionconserved in zinc carboxypeptidases and the N-glycosylation site areindcated in FIG. 134. Clone DNA66669-1597 has been deposited with theATCC and is assigned ATCC deposit no. 203272. The full-length PRO1339protein shown in FIG. 134 has an estimated molecular weight of about47,351 daltons and a pI of about 6.61.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 134 (SEQ ID NO:234), revealed sequence identity betweenthe PRO1339 amino acid sequence and the following Dayhoff sequences(data incorporated herein): P_W01505, CBP1_HUMAN, HSA224866_(—)1,P_R90293, YHT2_YEAST, CEF02D8_(—)4, CEW01A8_(—)6, P_W36815,HSU83411_(—)1 and CBPN_HUMAN.

Example 71 Isolation of cDNA Clones Encoding Human PRO1337

Using the method described in Example 1 above, a single Incyte EST wasidentified (EST No. 1747546) and also referred to herein as “DNA4417”.To assemble a consensus sequence, repeated cycles of BLAST and phrapwere used to extend the DNA4417 sequence as far as possible using thesources of EST sequences discussed above. The consensus sequence isdesignated herein as “DNA45669”. Based on the DNA45669 consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO1337.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primers: CAACCATGCAAGGACAGGGCAGG (45669.f1; SEQ ID    NO:237) and CTTTGCTGTTGGCCTCTGTGCTCCCAACCATGCAAGGACAGGGCAGG    (45669.r1; SEQ ID NO:238);-   reverse PCR primers: TGACTCGGGGTCTCCAAAACCAGC (45669.r1; SEQ ID    NO:239) and GGTATAGGCGGAAGGCAAAGTCGG (45669.r2; SEQ ID NO:240);

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA45669 sequence which had the followingnucleotide sequence:

-   hybridization probe:    GGCATCTTACCTTTATGGAGTACTCTTTGCTGTTGGCCTCTGTGCTCC (45669.p1; SEQ ID    NO:241).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1337 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1337 (designated herein as DNA66672-1586[FIG. 135, SEQ ID NO:235]; and the derived protein sequence for PRO1337.

The entire coding sequence of PRO1337 is shown in FIG. 135 (SEQ IDNO:235). Clone DNA66672-1586 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 60-62and an apparent stop codon at nucleotide positions 1311-1313. Thepredicted polypeptide precursor is 417 amino acids long. The full-lengthPRO1337 protein shown in FIG. 136 has an estimated molecular weight ofabout 46,493 daltons and a pI of about 9.79.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 136 (SEQ ID NO:236) revealed significant homology betweenthe PRO1337 amino acid sequence and the Dayhoff sequence THBG_HUMAN.Homology was also found between the PRO1337 amino acid sequence and thefollowing Dayhoff sequences: KAIN_HUMAN, HSACT1_(—)1, IPSP_HUMAN,G02081, HAMHPP_(—)1, CP16^(—)RAT, S31507, AB000547_(—)1, and KBP_MOUSE.

Clone DNA66672-1586 was deposited with the ATCC on Sep. 22, 1998, and isassigned ATCC deposit no. 203265.

Example 72 Isolation of cDNA Clones Encoding Human PRO1342

A cDNA sequence isolated in the amylase screen described in Example 2above is herein designated DNA43203. The DNA43203 sequence was thencompared to a variety of expressed sequence tag (EST) databases whichincluded public EST databases (e.g., GenBank) and proprietary EST DNAdatabases (LIFESEQTM, Incyte Pharmaceuticals, Palo Alto, Calif.;Genentech, South San Francisco, Calif.) to identify existing homologies.The homology search was performed using the computer program BLAST orBLAST2 (Altshul et al., Methods in Enzymology 266: 460-480 (1996)).Those comparisons resulting in a BLAST score of 70 (or in some cases 90)or greater that did not encode known proteins were clustered andassembled into consensus DNA sequences with the program “phrap” (PhilGreen, University of Washington, Seattle, Wash.). The consensus sequenceobtained therefrom is designated herein as “DNA48360”.

Based on the DNA48360 sequence, oligonucleotide probes were generatedand used to screen a human esophageal tissue library prepared asdescribed in paragraph 1 of Example 2 above. The cloning vector waspRK5B (pRK5B is a precursor of pRK5D that does not contain the SfiIsite; see, Holmes et al., Science, 253: 1278-1280 (1991)), and the cDNAsize cut was less than 2800 bp.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: 5′-GAAGCACCAGCCTTTATCTCTTCACC-3′ (48360.f1; SEQ    ID NO:244)-   reverse PCR primer: 5′-GTCAGAGTTGGTGGCTGTGCTAGC-3′ (48360.r1; SEQ ID    NO:245)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the DNA48360 sequence which had the following    nucleotide sequence:-   hybridization probe:    5′GGACCCAGGCATCTTGCTTTCCAGCCACAAAGAGACAGATGAAGATGC-3 (48360.p1; SEQ    ID NO:246)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1342 gene using the probe oligonucleotideand one of the PCR primers.

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 239-241, and a stop signal at nucleotide positions 2027-2029(FIG. 137; SEQ ID NO:242). The predicted polypeptide precursor is 596amino acids long has a calculated molecular weight of approximately57,173 daltons and an estimated pI of approximately 4.82. Additionalfeatures include: signal sequence at about amino acids 1-20; atransmembrane domain at about amino acids 510-532; a potentialN-glycosylation site at about amino acids 25-28; a glycosaminoglycanattachment site at about amino acids 325-328; and bacterialice-nucleation protein octamer repeats at about amino acids 284-337,404-457, 254-307, 359-412, 194-247, 239-292, 299-352, 134-187, 314-367,and 164-217.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 138 (SEQ ID NO:243), evidenced some homology between thePRO1342 amino acid sequence and the following Dayhoff sequences:CELZC178_(—)2, LMSAP2GN_(—)1, D88734_, AMYH_YEAST, MMDSPPG_(—)1,VGLX_HSVEB, S52714, CELF59A6_(—)5, CELK06A9_(—)3, and YM96_YEAST.

Clone DNA66674-1599 was deposited with the ATCC on Sep. 22, 1998, and isassigned ATCC deposit no. 203281.

Example 73 Isolation of cDNA Clones Encoding Human PRO1343

A cDNA sequence isolated in the amylase screen described in Example 2above was found, by the WU-BLAST2 sequence alignment computer program,to have no significant sequence identity to any known human encodingnucleic acid. This cDNA sequence is herein designated DNA48921. Probeswere generated from the sequence of the DNA48921 molecule and used toscreen a human smooth muscle cell tissue library prepared as describedin paragraph 1 above. The cloning vector was pRK5B (pRK5B is a precursorof pRK5D that does not contain the SfiI site; see, Holmes et al.,Science, 253: 1278-1280 (1991)), and the cDNA size cut was less than2800 bp.

The oligonucleotide probes employed were as follows:

-   forward PCR primer (48921.f1) 5′-CAATATGCATCTTGCACGTCTGG-3′ (SEQ ID    NO:249)-   reverse PCR primer (48921.r1) 5′-AAGCTTCTCTGCTTCTTCCTTTCCTGC-3′ (SEQ    ID NO:250)-   hybridization probe (48921.p1)    5′-TGACCCCATTGAGAAGGTCATTGAAGGGATCAACCGAGGGCTG-3′ (SEQ ID NO:251)

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 71-73 and a stop signal at nucleotide positions 812-814 (FIG.139, SEQ ID NO:247). The predicted polypeptide precursor is 247 aminoacids long, has a calculated molecular weight of approximately 25,335daltons and an estimated pI of approximately 7.0. Analysis of thefull-length PRO1343 sequence shown in FIG. 140 (SEQ ID NO:248) evidencesthe presence of the following: a signal peptide from about amino acid 1to about amino acid 25 and a homologous region to circumsporozoiterepeats from about amino acid 35 to about amino acid 225. CloneDNA66675-1587 has been deposited with ATCC on Sep. 22, 1998 and isassigned ATCC deposit no. 203282.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 140 (SEQ ID NO:248), evidenced significant homologybetween the PRO1343 amino acid sequence and the following Dayhoffsequences: CSP_PLACC, CEF25H8_(—)2, U88974_(—)40, BNAMRNAA_(—)1,BOBOPC3_(—)1, S58135, AF061832_(—)1, BHU52040_(—)1, HUMPROFILE_(—)1 andMTV023_(—)14.

Additionally, an Incyte EST clone (Incyte EST clone no. 4701148) havinghomology to the DNA48921 sequence was obtained and the insert sequenced,thereby giving rise to the DNA66675-1587 sequence shown in FIG. 139.

Example 74 Isolation of cDNA Clones Encoding Human PRO1480

Using the methods described in Example 1 above, Incyte EST Nos. 550415and 1628847 were identified as sequences of interest having BLAST scoresof 70 or greater that did not encode known proteins. These sequenceswere clustered and assembled into a consensus DNA sequence with theprogram “phrap” (Phil Green, University of Washington, Seattle, Wash.).This consensus sequence is designated herein as “DNA1395”. In addition,the “DNA1395” consensus sequence was extended using repeated cycles ofBLAST and phrap to extend the consensus sequence as far as possibleusing the sources of EST sequences discussed above. The extendedconsensus sequence is designated herein as “DNA40642”. Based on theDNA40642 consensus sequence, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence of interest,and 2) for use as probes to isolate a clone of the full-length codingsequence for PRO1480.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: AGCCCGTGCAGAATCTGCTCCTGG (40642.f1; SEQ ID    NO:254)-   reverse PCR primers: TGAAGCCAGGGCAGCGTCCTCTGG (40642.r1; SEQ ID    NO:255); GTACAGGCTGCAGTTGGC (40642.r2; SEQ ID NO:256)

Additionally, synthetic oligonucleotide hybridization probes wereconstructed from the consensus DNA40642 sequence which had the followingnucleotide sequence:

-   hybridization probes: AGAAGCCATGTGAGCAAGTCCAGTTCCAGCCCAACACAGTG    (40642.p1; SEQ ID NO:257);    GAGCTGCAGATCTTCTCATCGGGACAGCCCGTGCAGAATCTGCTC (40642.p2; SEQ ID    NO:258).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1480 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1480, designated herein as DNA67962-1649[FIG. 141, SEQ ID NO:252]; and the derived protein sequence for PRO1480.

The entire coding sequence of PRO1480 is shown in FIG. 141 (SEQ IDNO:252). Clone DNA67962-1649 contains a single open reading frame withan apparent translational initiation site at nucleotide positions241-243 and an apparent stop codon at nucleotide positions 2752-2754.The predicted polypeptide precursor is 837 amino acids long. Thefull-length PRO1480 protein shown in FIG. 142 has an estimated molecularweight of about 92,750 daltons and a pl of about 7.04. Additionalfeatures include: transmembrane domains at about amino acids 23-46 (typeII) and 718-738; potential N-glycosylation sites at about amino acids69-72, 96-99, 165-168, 410-413, 525-528, and 630-633; and a leucinezipper pattern at about amino acids 12-33.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 142 (SEQ ID NO:253), revealed significant homology betweenthe PRO1480 amino acid sequence and Dayhoff sequence I48746. Homologywas also shown between the PRO1480 amino acid sequence and the followingDayhoff sequences: S66498; P_W17658; MMU69535_(—)1; HSU60800_(—)1;I48745; A49069; I48747; GGU28240_(—)1; and AF022946_(—)1.

Clone DNA67962-1649 has been deposited with ATCC and is assigned ATCCdeposit no. 203291.

Example 75 Isolation of cDNA Clones Encoding Human PRO1487

A single Merck EST, HSC21D011, referred herein as “DNA8208”, wasidentified as an EST of interest having a BLAST score of 70 or greaterthat did not encode a known protein as described in Example 1 above. TheDNA8208 sequence was extended using repeated cycles of BLAST and theprogram “phrap” (Phil Green, University of Washington, Seattle, Wash.)to extend the sequence as far as possible using the sources of ESTsequences discussed above. The resulting consensus sequence isdesignated herein as “DNA68836”. Based on the DNA68836 consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO1487.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: GTGCCACTACGGGGTGTGGACGAC (54209.f1; SEQ ID    NO:261) and-   reverse PCR primer TCCCATTTCTTCCGTGGTGCCCAG (54209.r1; SEQ ID    NO:262)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA68836 sequence which had the followingnucleotide sequence:

-   hybridization probe CCAGAAGAAGTCCTTCATGATGCTCAAGTACATGCACGACCACTAC    (54209.p1; SEQ ID NO:263)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1487 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1487 (designated herein as DNA68836-1656(FIGS. 143A-B; SEQ ID NO:259) and the derived protein sequence forPRO1487 (FIG. 144; SEQ ID NO:260).

The entire coding sequence of PRO1487 is shown in FIGS. 143A-B (SEQ IDNO:259). Clone DNA68836-1656 contains a single open reading frame withan apparent translational initiation site at nucleotide positions489-491 and an apparent stop codon at nucleotide positions 2895-2897.The predicted polypeptide precursor is 802 amino acids long Thefull-length PRO1487 protein shown in FIG. 144 has an estimated molecularweight of about 91,812 daltons and a pI of about 9.52. Additionalfeatures include a signal peptide at about amino acids 1-23; potentialN-glycosylation sites at about amino acids 189-192, 623-626, and796-799; and a cell attachment sequence at about amino acids 62-64.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 144 (SEQ ID NO:260), revealed significant homology betweenthe PRO1487 amino acid sequence and the following Dayhoff sequences:CET24D1_(—)1, S44860, CELC02H6_(—)1, CEC38H2_(—)3, CELC17A2_(—)5,CET09E11_(—)10, CEE03H4_(—)3, CELT22B11_(—)3, GGU82088_(—)1, andCEF56H6_(—)1.

Clone DNA68836-1656 was deposited with the ATCC on Nov. 3, 1998, and isassigned ATCC deposit no. 203455.

Example 76 Isolation of cDNA Clones Encoding Human PRO1418

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from an Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs was derived from a placenta tissuelibrary. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). The consensussequence obtained therefrom is herein designated DNA58845.

In light of the sequence homology between the DNA58845 sequence and anEST included in Incyte clone 1306026, that clone was purchased and thecDNA insert was obtained and sequenced. The sequence of this cDNA insertis shown in FIG. 145 and is herein designated as DNA68864-1629.

The full length clone shown in FIG. 145 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 138-140 and ending at the stop codon found at nucleotidepositions 1188-1190 (FIG. 145; SEQ ID NO:264). The predicted polypeptideprecursor (FIG. 146, SEQ ID NO:265) is 350 amino acids long with asignal peptide at about amino acids 1-19 of SEQ ID NO:265. PRO1418 has acalculated molecular weight of approximately 39,003 daltons and anestimated pI of approximately 5.59. Clone DNA68864-1629 was depositedwith the ATCC on Sep. 22, 1998 and is assigned ATCC deposit no. 203276.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 146 (SEQ ID NO:265), revealed sequence identity betweenthe PRO1418 amino acid sequence and the following Dayhoff sequences(data incorporated herein): AGA1_HAEIN (immunoglobulin a1 proteaseprecursor), P_WO3740, CELT23E7_(—)1, SSN6_YEAST, MMPININ_(—)1,AB00993_(—)1, P_R52601, S22624, A10377_(—)1 and MUA1_XENLA.

Example 77 Isolation of cDNA Clones Encoding Human PRO1472

An Incyte sequence was identified and put in a computer to determinewhether it had homology with other proteins in databases. The ESTdatabases included public EST databases (e.g., GenBank), and theproprietary EST database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto,Calif.). The search was performed using the computer program BLAST orBLAST2 [Altschul et al., Methods in Enzymology, 266: 460-480 (1996)] asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Those comparisons resulting in a BLAST score of 70(or in some cases, 90) or greater that did not encode known proteinswere clustered and assembled into consensus DNA sequences with theprogram “phrap” (Phil Green, University of Washington, Seattle, Wash.).

A consensus DNA sequence encoding PRO1472 was assembled relative toother EST sequences using phrap. This consensus sequence is designatedherein “DNA62824”. Based on the DNA62824 consensus sequence and otherdiscoveries and information provided herein, the Incyte clone includingEST 1579843 (from a duodenal tissue library) found in the assembly waspurchased and sequenced in full.

Sequencing provided the entire coding sequence of PRO1472 as shown inFIG. 147 (SEQ ID NO:266). Clone DNA68866-1644 contains a single openreading frame with an apparent translational initiation site atnucleotide positions 134-136 and an apparent stop codon at nucleotidepositions 1532-1534 of SEQ ID NO:266. The predicted polypeptideprecursor is 466 amino acids long. As indicated in FIG. 148, the signalpeptide is at about amino acid positions 1-17 and the transmembranedomains are at about positions 131-150 and 235-259 of SEQ ID NO:267.Clone DNA68866-1644 has been deposited with ATCC and is assigned ATCCdeposit no. 203283. The full-length PRO1472 protein shown in FIG. 148has an estimated molecular weight of about 52,279 daltons and a pI ofabout 6.16.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 148 (SEQ ID NO:267), revealed sequence identity betweenthe PRO1472 amino acid sequence and the following Dayhoff sequences(data incorporated herein): BUTY_HUMAN, HS45P21_(—)1, HS45P21_(—)3,HS45P21_(—)5, HS45P21_(—)4, HSU90142_(—)1, HSU90546_(—)1, AF033107_(—)1,MMHC135G15_(—)7 and HSB73_(—)1.

Example 78 Isolation of cDNA Clones Encoding Human PRO1461

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated Incyte EST Cluster No. 159103, and also referred toherein as “DNA 10747”. The DNA 10747 sequence was then compared to avariety of EST databases which included public EST databases (e.g.,GenBank) and the LIFESEQ® database, to identify existing homologies. Thehomology search was performed using the computer program BLAST or BLAST2(Altshul et al., Methods in Enzymology 266: 460-480 (1996)). Thosecomparisons resulting in a BLAST score of 70 (or in some cases 90) orgreater that did not encode known proteins were clustered and assembledinto a consensus DNA sequence with the program “phrap” (Phil Green,University of Washington, Seattle, Wash.). One or more of the ESTs usedin the assembly was derived from a library constructed from pancreatictumor tissue. The consensus sequence obtained therefrom is hereindesignated “DNA59553”.

In light of the sequence homology between the DNA59553 sequence and anEST sequence contained within Incyte EST no. 2944541, the EST clone waspurchased and the cDNA insert was obtained and sequenced. The sequenceof this cDNA insert is shown in FIG. 149 and is herein designated asDNA68871-1638.

The full length clone shown in FIG. 149 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 32-34 and ending at the stop codon found at nucleotidepositions 1301-1303 (FIG. 149; SEQ ID NO:268). The predicted polypeptideprecursor (FIG. 150, SEQ ID NO:269) is 423 amino acids long. PRO1461 hasa calculated molecular weight of approximately 47,696 daltons and anestimated pI of approximately 8.96. Additional features include: a typeII transmembrane domain at about amino acids 21-40; an ATP/GTP-bindingsite motif A (P-loop) at about amino acids 359-366; a trypsin familyhistidine active site at about amino acids 228-233; potentialN-myristoylation sites at about amino acids 179-184, 213-218, 317-322,and 360-365; and potential N-glycosylation sites at about amino acids75-78, 166-169 and 223-226.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 150 (SEQ ID NO:269), revealed significant homology betweenthe PRO1461 amino acid sequence Dayhoff sequence no. P_R89435. Homologywas also found to exist between the PRO1461 amino acid sequence and thefollowing additional Dayhoff sequences: AB002134_(—)1, P_R89430,P_W22987, HEPS_MOUSE, ENTK_HUMAN, P_W22986. KAL_MOUSE, ACRO_PIG,p_R57283, and TRY7_ANOGA.

Clone DNA68871-68871 was deposited with the ATCC on Sep. 22, 1998, andis assigned ATCC deposit no. 203280.

Example 79 Isolation of cDNA Clones Encoding Human PRO1410

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 98502. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (LIFESEQ®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56451.

In light of the sequence homology between the DNA56451 sequence and anEST sequence contained within the Incyte EST clone no. 1257046, theIncyte EST clone 125046 was purchased and the cDNA insert was obtainedand sequenced. The sequence of this cDNA insert is shown in FIG. 151 andis herein designated as DNA68874-1622.

Clone DNA68874-1622 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 152-154and ending at the stop codon at nucleotide positions 866-868 (FIG. 151).The predicted polypeptide precursor is 238 amino acids long (FIG. 152).The full-length PRO1410 protein shown in FIG. 152 has an estimatedmolecular weight of about 25,262 daltons and a pI of about 6.44.Analysis of the full-length PRO1410 sequence shown in FIG. 152 (SEQ IDNO:271) evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 20, a transmembrane domain fromabout amino acid 194 to about amino acid 220 and a potentialN-glycosylation site from about amino acid 132 to about amino acid 135.Clone DNA68874-1622 has been deposited with ATCC on Sep. 22, 1998 and isassigned ATCC deposit no. 203277.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 152 (SEQ ID NO:271), evidenced significant homologybetween the PRO1410 amino acid sequence and the following Dayhoffsequences: I48652, P_R76466, HSMHC3W36A_(—)2, EPB4_HUMAN, P_R14256,EPA8_MOUSE, P_R77285, P_W13569, AF000560_(—)1, and ASF1_HELAN.

Example 80 Isolation of cDNA Clones Encoding Human PRO1568

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap to form an assembly as described in Example 1 above. Theconsensus sequence is designated herein “DNA54208”. Based on theDNA54208 consensus sequence, the assembly and other information anddiscoveries provided herein, a clone including an EST in the assemblywas ordered and sequenced. The EST is Incyte 3089490. Sequencing in fullgave the sequence shown in FIG. 153.

The entire coding sequence of PRO1568 is included in FIG. 153 (SEQ IDNO:272). Clone DNA68880-1676 contains a single open reading frame withan apparent translational initiation site at nucleotide positions208-210 and an apparent stop codon at nucleotide positions 1123-1125 ofSEQ ID NO:272. The predicted polypeptide precursor is 305 amino acidslong. The signal peptide, transmembrane regions, N-myristoylation andamidation sites are also indicated in FIG. 154. Clone DNA68880-1676 hasbeen deposited with the ATCC and is assigned ATCC deposit no. 203319.The full-length PRO1568 protein shown in FIG. 154 has an estimatedmolecular weight of about 35,383 daltons and a pI of about 5.99.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 154 (SEQ ID NO:273), revealed sequence identity betweenthe PRO1568 amino acid sequence and the following Dayhoff sequences(incorporated herein): AF089749_(—)1, AF054841_(—)1, NAG2_HUMAN,CD63_HUMAN, CD82_HUMAN, P_WO5732, P_R86834, A15_SHUMAN, P_W27333 andCD37_HUMAN.

Example 81 Isolation of cDNA Clones Encoding Human PRO1570

A consensus DNA sequence encoding PRO1570 was assembled relative toother EST sequences using phrap as described in Example 1 above to forman assemby. This consensus sequence is designated herein as “DNA65415”.Based on the DNA65415 consensus sequence and other discoveries andinformation provided herein, the clone including Incyte EST 3232285(from a uterine/colon cancer tissue library) was purchased and sequencedin full which gave SEQ ID NO:274.

The entire coding sequence of PRO1570 is included in FIG. 155 (SEQ IDNO:274). Clone DNA68885-1678 contains a single open reading frame withan apparent translational initiation site at nucleotide positions210-212 and an apparent stop codon at nucleotide positions 1506-1508 ofSEQ ID NO:274. The predicted polypeptide precursor is 432 amino acidslong. FIG. 275 shows a number of motifs. Clone DNA68885-1678 has beendeposited with the ATCC and is assigned ATCC deposit no. 203311. Thefull-length PRO1570 protein shown in FIG. 156 has an estimated molecularweight of about 47,644 daltons and a pI of about 5.18.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 156 (SEQ ID NO:275), revealed sequence identity betweenthe PRO1570 amino acid sequence and the following Dayhoff sequences(incorporated herein): P_W22986, TMS2_HUMAN, HEPS_HUMAN, P_R89435,AB002134_(—)1, KAL_MOUSE, ACRO_HUMAN, GEN12917, AF045649_(—)1, andP_W34285.

Example 82 Isolation of cDNA Clones Encoding Human PRO1317

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “Consen8865”. In addition, the Consen8865 consensussequence was extended using repeated cycles of BLAST and phrap to extendthe consensus sequence as far as possible using the sources of ESTsequences discussed above. The extended consensus sequence is designatedherein as “DNA63334”. Based on the DNA63334 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1317.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: CTGCTGGTGAAATCTGGCGTGGAG (63334.f1; SEQ ID    NO:278); and-   reverse PCR primer: GTCTGGTCCTGGCTGTCCACCCAG (63334.r1; SEQ ID    NO:279).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA63334 sequence which had the followingnucleotide sequence:

-   hybridization probe: CATCTTGTCATGTACCTGGGAACCACCACAGGGTCGCTCCACAAG    (63334.p1; SEQ ID NO:280).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1317 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human hippocampal tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1317 (designated herein as DNA71166-1685[FIG. 157. SEQ ID NO:276]; and the derived protein sequence for PRO1317.

The entire coding sequence of PRO1317 is shown in FIG. 157 (SEQ IDNO:276). Clone DNA71166-1685 contains a single open reading frame withan apparent translational initiation site at nucleotide positions105-107 and an apparent stop codon at nucleotide positions 2388-2390.The predicted polypeptide precursor is 761 amino acids long and has anestimated molecular weight of about 83,574 daltons and a pI of about6.78.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 158 (SEQ ID NO:277), revealed significant homology betweenthe PRO1317 amino acid sequence and Dayhoff sequence no. I48745.Homology was also revealed between the PRO1317 amino acid sequence thefollowing Dayhoff sequences: I48746, GEN13418, P_W58540, P_(—)217657.MUSC1_(—)1, P_(—)471380, U73167_(—)5, HSU33920_(—)1, and GG828240_(—)1.

Clone DNA71166-1685 was deposited with the ATCC on Oct. 20, 1998, and isassigned ATCC deposit no. 203355.

Example 83 Isolation of cDNA Clones Encoding Human PRO1780

The DNA63837.init sequence was obtained as described in Example 1 aboveand was extended using repeated cycles of BLAST and the program “phrap”(Phil Green, University of Washington, Seattle) to extend the consensussequence as far as possible using the sources of EST sequences discussedabove. The extended consensus sequence is designated herein as“DNA63837”. Based on the DNA63837 consensus sequence, oligonucleotideswere synthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate a clone ofthe full-length coding sequence for PRO1780.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: TGCCTTTGCTCACCTACCCCAAGG (63837.f1; SEQ ID    NO:283)-   reverse PCR primer: TCAGGCTGGTCTCCAAAGAGAGGG (63837.r1; SEQ ID    NO:284)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA63837 sequence which had the followingnucleotide sequence:

-   hybridization probe: CCCAAAGATGTCCACCTGGCTGCAAATGTGAAAATTGTGGACTGG    (63837.p1; SEQ ID NO:285)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1780 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from a human fetal kidney.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1780 (designated herein as DNA71169-1709[FIG. 159, SEQ ID NO:281]; and the derived protein sequence for PRO1780.

The entire coding sequence of PRO1780 is shown in FIG. 159 (SEQ IDNO:281). Clone DNA71169-1709 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 68-70and an apparent stop codon at nucleotide positions 1637-1639. Thepredicted polypeptide precursor is 523 amino acids long. The full-lengthPRO1780 protein shown in FIG. 160 has an estimated molecular weight ofabout 59,581 daltons and a pI of about 8.68. Additional features includea signal peptide sequence at about amino acids 1-19; a transmembranedomain at about amino acids 483-504; tyrosine phosphorylation sites atabout amino acids 68-74 and 425-433; N-myristoylation sites at aboutamino acids 16-21, 301-206, 370-375, and 494-499; and a leucine zipperpattern at about amino acids 493-514.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 160 (SEQ ID NO:282), revealed significant homology betweenthe PRO1780 amino acid sequence and the following Dayhoff sequences:UDA2_RABIT, CGT_HUMAN, UD11_HUMAN, P_R26153, UDB1_RAT, HSU59209_(—)1,AB010872_(—)1, UDB5_MOUSE, UDB8_HUMAN, and UD14_HUMAN.

Clone DNA71169-1709 was deposited with the ATCC on Nov. 17, 1998, and isassigned ATCC deposit no. 203467.

Example 84 Isolation of cDNA Clones Encoding Human PRO1486

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1above. This consensus sequence isdesignated herein “DNA48897”. Based on the DNA48897 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1486.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′AGGCAGCCACCAGCTCTGTGCTAC3′ (SEQ ID NO:288); and-   reverse PCR primer 5′CAGAGAGGGAAGATGAGGAAGCCAGAG3′ (SEQ ID NO:289).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA48897 sequence which had the followingnucleotide sequence:

-   hybridization probe 5′CTGTGCTACTGCCCTTGGACCCTGGGGACCGAGTGTCTCTGC3′    (SEQ ID NO:290).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1486 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from a human adenocarcinoma cell line.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1486 and the derived protein sequencefor PRO1486.

The entire coding sequence of PRO1486 is included in FIG. 161 (SEQ IDNO: 286). Clone DNA71180-1655 contains a single open reading frame withan apparent translational initiation site at nucleotide positions472-474 and an apparent stop codon at nucleotide positions 1087-1089 ofSEQ ID NO:286. The predicted polypeptide precursor is 205 amino acidslong. The signal peptide is at about amino acids 1-32 of SEQ ID NO:287.Regions similar to those of C1q and an N-glycosylationi site are locatedas indicated in FIG. 162. Clone DNA71180-1655 has been deposited withthe ATCC and is assigned ATCC deposit no. 203403. The full-lengthPRO1486 protein shown in FIG. 162 has an estimated molecular weight ofabout 21,521 daltons and a pI of about 7.07.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the fill-length sequenceshown in FIG. 162 (SEQ ID NO:287), revealed sequence identity betweenthe PRO1486 amino acid sequence and the following Dayhoff sequences:CERB_HUMAN, CERL_RAT, GEN11893, P_R22263, CA18_HUMAN, CIQC_HUMAN,AF054891_(—)1, A57131, HUMCIQb2_(—)1, ACR3_MOUSE.

Example 85 Isolation of cDNA Clones Encoding Human PRO1433

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA45230. Based on the DNA45230 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1433.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (45230.f1) 5′-GCTGACCTGGTTCCCATCTACTCC-3′ (SEQ ID    NO:293)-   reverse PCR primer (45230.r1) 5′-CCCACAGACACCCATGACACTTCC-3′ (SEQ ID    NO:294)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA45230 sequence which had the    following nucleotide sequence-   hybridization probe (45230.p1)    5′-AAGAATGAATTGTACAAAGCAGGTGATCTTCGAGGAGGGCTCCTGGGGCC-3′ (SEQ ID    NO:295)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1433 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human adrenal gland tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1433 (designated herein as DNA71184-1634[FIG. 163, SEQ ID NO: 291]; and the derived protein sequence forPRO1433.

The entire nucleotide sequence of DNA71184-1634 is shown in FIG. 163(SEQ ID NO:291). Clone DNA71184-1634 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 185-187 and ending at the stop codon at nucleotide positions1349-1351 (FIG. 163). The predicted polypeptide precursor is 388 aminoacids long (FIG. 164). The full-length PRO1433 protein shown in FIG. 164has an estimated molecular weight of about 43,831 daltons and a pI ofabout 9.64. Analysis of the full-length PRO1433 sequence shown in FIG.164 (SEQ ID NO:292) evidences the presence of the following: atransmembrane domain from about amino acid 76 to about amino acid 97,potential N-glycosylation sites from about amino acid 60 to about aminoacid 63, from about amino acid 173 to about amino acid 176 and fromabout amino acid 228 to about amino acid 231 and potentialN-myristolation sites from about amino acid 10 to about amino acid 15,from about amino acid 41 to about amino acid 46, from about amino acid84 to about amino acid 89, from about amino acid 120 to about amino acid125, from about amino acid 169 to about amino acid 174, from about aminoacid 229 to about amino acid 234, from about amino acid 240 to aboutamino acid 245, from about amino acid 318 to about amino acid 323 andfrom about amino acid 378 to about amino acid 383. Clone DNA71184-1634has been deposited with ATCC on Sep. 22, 1998 and is assigned ATCCdeposit no. 203266.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST sequence alignment analysis of the full-length sequence shownin FIG. 164 (SEQ ID NO:292), evidenced significant homology between thePRO1433 amino acid sequence and the following Dayhoff sequences:CELW01A11_(—)4, CEF59A1_(—)4, S67138, MTV050_(—)3, S75135 and S12411.

Example 86 Isolation of cDNA Clones Encoding Human PRO1490

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA67006. Based on the DNA67006 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1490.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (67006.f1) 5′-CTTCCTCTGTGGGTGGACCATGTG-3′ (SEQ ID    NO:298)-   reverse PCR primer (67006.r1) 5′-GCCACCTCCATGCTAACGCGG-3′ (SEQ ID    NO:299)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA67006 sequence which had the    following nucleotide sequence-   hybridization probe (67006.p1)    5′-CCAAGGTCCTCGCTAAGAAGGAGCTGCTCTACGTGCCCCTCATCG-3′ (SEQ ID NO:300)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used, toisolate clones encoding the PRO1490 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human adrenal gland tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1490 (designated herein as DNA71213-1659[FIG. 165, SEQ ID NO:296]; and the derived protein sequence for PRO1490.

The entire nucleotide sequence of DNA71213-1659 is shown in FIG. 165(SEQ ID NO:296). Clone DNA71213-1659 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 272-274 and ending at the stop codon at nucleotide positions1376-1378 (FIG. 165). The predicted polypeptide precursor is 368 aminoacids long (FIG. 166). The full-length PRO1490 protein shown in FIG. 166has an estimated molecular weight of about42,550 daltons and a pI ofabout 9.11. Analysis of the full-length PRO1490 sequence shown in FIG.166 (SEQ ID NO:297) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 25, transmembranedomains from about amino acid 307 to about amino acid 323 and from aboutamino acid 335 to about amino acid 352 and tyrosine kinasephosphorylation sites from about amino acid 160 to about amino acid 168and from about amino acid 161 to about amino acid 168. CloneDNA71213-1659 has been deposited with ATCC on Oct. 27, 1998 and isassigned ATCC deposit no. 203401.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 166 (SEQ ID NO:297), evidenced significant homologybetween the PRO1490 amino acid sequence and the following Dayhoffsequences: A52744_(—)1, S60478, P_R99249, P_R59712, YBP2_YEAST, S54641,CELTO5H4_(—)15, CELF28B3_(—)1, CELZK40_(—)1 and YIHG_ECOLI.

Example 87 Isolation of cDNA Clones Encoding Human PRO1482

A cDNA clone (DNA71234-1651) encoding a native human PRO1482 polypeptidewas identified by a yeast screen, in a human adrenal gland cDNA librarythat preferentially represents the 5′ ends of the primary cDNA clones.

The full-length DNA71234-1651 clone shown in FIG. 167 contains a singleopen reading frame with an apparent translational initiation site atnucleotide positions 33-35 and ending at the stop codon at nucleotidepositions 462-464 (FIG. 167). The predicted polypeptide precursor is 143amino acids long (FIG. 168). The full-length PRO1482 protein shown inFIG. 168 has an estimated molecular weight of about 15,624 daltons and apI of about 9.58. Analysis of the full-length PRO1482 sequence shown inFIG. 168 (SEQ ID NO:302) evidences the presence of the following: asignal peptide from about amino acid 1 to about amino acid 28. CloneDNA71234-1651 has been deposited with ATCC on Oct. 27, 1998 and isassigned ATCC deposit no. 203402.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 168 (SEQ ID NO:302), evidenced significant homologybetween the PRO1482 amino acid sequence and the following Dayhoffsequences: A18267_(—)3.

Example 88 Isolation of cDNA Clones Encoding Human PRO1446

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs was derived from a pancreatic isletcell library. The homology search was performed using the computerprogram BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (orin some cases 90) or greater that did not encode known proteins wereclustered and assembled into a consensus DNA sequence with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.). Theconsensus sequence obtained therefrom is herein designated DNA56514.

In light of the sequence homology between the DNA56514 sequence and anEST sequence contained within the Incyte EST 2380344, the cloneincluding this EST was purchased and the cDNA insert was obtained andsequenced. The sequence of this cDNA insert is shown in FIG. 169 and isherein designated as DNA71277-1636.

The full length clone shown in FIG. 169 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 152-154 and ending at the stop codon found at nucleotidepositions 479-481 (FIG. 169; SEQ ID NO:303). The predicted polypeptideprecursor (FIG. 170, SEQ ID NO:304) is 109 amino acids long with asignal peptide at about amino acids 1-15 of SEQ ID NO:304. PRO1446 has acalculated molecular weight of approximately 11,822 daltons and anestimated pI of approximately 8.63. Clone DNA71277-1636 was depositedwith the ATCC on Sep. 22, 1998 and is assigned ATCC deposit no. 203285.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 170 (SEQ ID NO:304), revealed sequence identity betweenthe PRO1446 amino acid sequence and the following Dayhoff sequences(data incorporated herein): P53_CANFA, P53_FELCA, LRP1_HSV1F,OSU57338_(—)1, S75842, P_P93722, AF002189_(—)1, B70408, S54309 andS53365. The first in this list is further described in Kraegel, et al.,Cancer Lett., 92(2): 181-186 (1995).

Example 89 Isolation of cDNA Clones Encoding Human PRO1558

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated Incyte EST cluster sequence no. 86390. This ESTcluster sequence was then compared to a variety of expressed sequencetag (EST) databases which included public EST databases (e.g., GenBank)and a proprietary EST DNA database (LIFESEQ®, Incyte Pharmaceuticals,Palo Alto, Calif.) to identify existing homologies. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA58842.

In light of the sequence homology between the DNA58842 sequence and anEST sequence contained within the Incyte EST clone no. 3746964, theIncyte EST clone no. 3746964 was purchased and the cDNA insert wasobtained and sequenced. The sequence of this cDNA insert is shown inFIG. 171 and is herein designated as DNA71282-1668.

Clone DNA71282-1668 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 84-86 andending at the stop codon at nucleotide positions 870-872 (FIG. 171). Thepredicted polypeptide precursor is 262 amino acids long (FIG. 172). Thefull-length PRO1558 protein shown in FIG. 172 has an estimated molecularweight of about 28,809 daltons and a pI of about 8.80. Analysis of thefull-length PRO1558 sequence shown in FIG. 172 (SEQ ID NO:306) evidencesthe presence of the following: a signal peptide from about amino acid 1to about amino acid 25, transmembrane domains from about amino acid 8 toabout amino acid 30 and from about amino acid 109 to about amino acid130, a potential N-glycosylation site from about amino acid 190 to aboutamino acid 193, a tyrosine kinase phosphorylation site from about aminoacid 238 to about amino acid 246, potential N-myristolation sites fromabout amino acid 22 to about amino acid 27, from about amino acid 28 toabout amino acid 33, from about amino acid 110 to about amino acid 115,from about amino acid 205 to about amino acid 210 and from about aminoacid 255 to about amino acid 260 and amidation sites from about aminoacid 31 to about amino acid 34 and from about amino acid 39 to aboutamino acid 42. Clone DNA71282-1668 has been deposited with ATCC on Oct.6, 1998 and is assigned ATCC deposit no. 203312.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 172 (SEQ ID NO:306), evidenced significant homologybetween the PRO1558 amino acid sequence and the following Dayhoffsequences: AF075724_(—)2, MXU24657_(—)3, CAMT_EUCGU, MSU20736_(—)1,P_R29515, B70431, JC4004, CEY32B12A_(—)3, CELF53B3_(—)2 and P_R13543.

Example 90 Isolation of cDNA Clones Encoding Human PRO1604

An expressed sequence tag (EST) DNA database (LIFESEQ®, IncytePharmaceuticals, Palo Alto, Calif.) was searched. Incyte EST No. 3550440was identified as having homology to HDGF. EST No. 3550440 was thencompared to various EST databases including public EST databases (e.g.GenBank), and the LIFESEQ® database, to identify homologous ESTsequences. The search was performed using the computer program BLAST orBLAST2 [Altschul et al., Methods in Enzymology, 266: 460-480 (1996)].Those comparisons resulting in a BLAST score of 70 (or in some cases,90) or greater that did not encode known proteins were clustered andassembled into consensus DNA sequences with the program “phrap” (PhilGreen, University of Washington, Seattle, Wash.). This consensussequence is designated herein “DNA67237”.

In light of the sequence homology between the DNA67237 sequence and ESTno. 3367060 from the LIPESEQ® database, the clone containing Incyte ESTNo. 3367060 was purchased and the cDNA insert was obtained and sequencedto obtain the entire coding sequence of PRO1604 which is shown in FIG.173 (SEQ ID NO:307).

Clone DNA71286-1687 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 65-67 andan apparent stop codon at nucleotide positions 2078-2080. The predictedpolypeptide precursor is 671 amino acids long. The full-length PRO1604protein shown in FIG. 174 has an estimated molecular weight of about74.317 daltons and a pI of about 7.62. Additional features include asignal peptide at about amino acids 1-13; potential cAMP- andcGMP-dependent protein kinase phosphorylation sites at about amino acids156-159, 171-174, and 451-454; potential N-myristoylation sites at aboutamino acids 46-51, 365-370, and 367-372; and a cell attachment sequenceat about amino acids 661-663.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 174 (SEQ ID NO:308), revealed significant homology betweenthe PRO1604 amino acid sequence and Dayhoff sequence no. P_W37483.Homology was also shown between the PRO1604 amino acid sequence and thefollowing additional Dayhoff sequences; AF063020_(—)1, P_R66727,P_W37482, JC5661, CEC25A1_(—)11, CEU33058_(—)1, I38073, MST2_DROHY, andHSATRX36_(—)1.

Clone DNA71286-1687 was deposited with the ATCC on Oct. 20, 1998, and isassigned ATCC deposit no. 203357.

Example 91 Isolation of cDNA Clones Encoding Human PRO1491

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA67202. Based on the DNA67202 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1491.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (67202.f1) 5′-CAACGCAGCCGTGATAAACAAGTGG-3′ (SEQ    ID NO:311)-   reverse PCR primer (67202.r1) 5′-GCTTGGACATGTACCAGGCCGTGG-3′ (SEQ ID    NO:312)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA67202 sequence which had the    following nucleotide sequence-   hybridization probe (67202.p1)    5′-GGCCAGACTGATTTGCTCAATTCCTGGAAGTGATGGGGCAGATAC-3′ (SEQ ID NO:313)

RNA for construction of the cDNA libraries was isolated from humanaortic endothelial cell tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1491 (designated herein as DNA71883-1660[FIG. 175, SEQ ID NO:309]; and the derived protein sequence for PRO1491.

The entire nucleotide sequence of DNA71883-1660 is shown in FIG. 175(SEQ ID NO:309). Clone DNA71883-1660 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 107-109 and ending at the stop codon at nucleotide positions2438-2440 (FIG. 175). The predicted polypeptide precursor is 777 aminoacids long (FIG. 176). The full-length PRO1491 protein shown in FIG. 176has an estimated molecular weight of about 89,651 daltons and a pI ofabout 7.97. Analysis of the full-length PRO1491 sequence shown in FIG.176 (SEQ ID NO:310) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 36, potentialN-glycosylation sites from about amino acid 139 to about amino acid 142,from about amino acid 607 to about amino acid 610 and from about aminoacid 724 to about amino acid 727, a tyrosine kinase phosphorylation sitefrom about amino acid 571 to about amino acid 576 and a gram-positivecocci surface protein anchoring hexapeptide sequence from about aminoacid 32 to about amino acid 37. Clone DNA71883-1660 has been depositedwith ATCC on Nov. 17, 1998 and is assigned ATCC deposit no. 203475.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 176 (SEQ ID NO:310), evidenced significant homologybetween the PRO1491 amino acid sequence and the following Dayhoffsequences: GGU28240_(—)1, MUSC1_(—)1, D49423, MMSEMH_(—)1,AB002329_(—)1, AF022947_(—)1, HSU33920_(—)1, HUMLUCA19_(—)1, G01856 andAF022946_(—)1.

Example 92 Isolation of cDNA Clones Encoding Human PRO1431

An expressed sequence tag (EST) DNA database (LIFESEQ®, IncytePharmaceuticals, Palo Alto, Calif.) was searched and an EST (isolatedfrom adult brain stem tissue) was identified (I370141, DNA66505) whichshowed homology to SH3. RNA for construction of cDNA libraries wasisolated from human bone marrow. A full length cDNA corresponding to theisolated EST was isolated using an in vitro cloning technique(DNA73401-1633) in pRK5.

The cDNA libraries used to isolate the cDNA clones encoding humanPRO1431 were constructed by standard methods using commerciallyavailable reagents such as those from Invitrogen, San Diego, Calif. ThecDNA was primed with oligo dT containing a NotI site, linked with bluntto SalI hemikinased adaptors, cleaved with NotI, sized appropriately bygel electrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI.

A cDNA clone was sequenced in entirety. The entire nucleotide sequenceof DNA73401-1633 (SEQ ID NO:314) is shown in FIG. 177. CloneDNA73401-1633 contains a single open reading frame with an apparenttranslational initiation site at about nucleotide positions 630632 and astop codon at about nucleotide positions 1740-1742. The predictedpolypeptide precursor encoded by DNA73401-1633 is 370 amino acids long.Clone DNA73401 (designated as DNA73402-1633) has been deposited withATCC and is assigned ATCC deposit no. 203273.

Based sequence alignment analysis (using the ALIGN computer program) ofthe full-length sequence, PRO1431 shows significant amino acid sequenceidentity to SH17_HUMAN, an SH3 containing protein known as SH3P17.Additional significant identity score were found with D89164_(—)1,AF032118_(—)1, EXLP_TOBAC, YHR4_YEAST, S46992, RATP130CAS_(—)2,AF043259_(—)1, RATP130CAS_(—)1 and MYSC_ACACA.

Example 93 Isolation of cDNA Clones Encoding Human PRO1563

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA67191. Based on the DNA67191 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1563.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (67191.f1) 5′-CCCTGAAGCTGCCAGATGGCTCC-3′ (SEQ ID    NO:318)-   reverse PCR primer (67191.r1) 5′-CTGTGCTCTTCGGTGCAGCCAGTC-3′ (SEQ ID    NO:319)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA67191 sequence which had the    following nucleotide sequence-   hybridization probe (67191.p1)    5′-CCACAGATGTGGTACTGCCTGGGGCAGTCAGCTTGCGCTACAG-3′ (SEQ ID NO:320)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1563 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human bone marrow tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1563 (designated herein as DNA73492-1671[FIGS. 179A-B, SEQ ID NO:316]; and the derived protein sequence forPRO1563.

The entire nucleotide sequence of DNA73492-1671 is shown in FIGS. 179A-B(SEQ ID NO:316). Clone DNA73492-1671 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 419-421 and ending at the stop codon at nucleotide positions2930-2932 (FIGS. 179A-B). The predicted polypeptide precursor is 837amino acids long (FIG. 180). The full-length PRO1563 protein shown inFIG. 180 has an estimated molecular weight of about 90,167 daltons and apI of about 8.39. Analysis of the full-length PRO1563 sequence shown inFIG. 180 (SEQ ID NO:317) evidences the presence of the following: asignal peptide from about amino acid 1 to about amino acid 48, apotential N-glycosylation site from about amino acid 68 to about aminoacid 71, glycosaminoglycan attachment sites from about amino acid 188 toabout amino acid 191 and from about amino acid 772 to about amino acid775, a cAMP-and cGMP-dependent protein kinase phosphorylation site fromabout amino acid 182 to about amino acid 185, a tyrosine kinasephosphorylation site from about amino acid 730 to about amino acid 736,potential N-myristolation sites from about amino acid 5 to about aminoacid 10, from about amino acid 19 to about amino acid 24, from aboutamino acid 121 to about amino acid 126, from about amino acid 125 toabout amino acid 130, from about amino acid 130 to about amino acid 135,from about amino acid 147 to about amino acid 152, from about amino acid167 to about amino acid 172, from about amino acid 168 to about aminoacid 173, from about amino acid 174 to about amino acid 179, from aboutamino acid 323 to about amino acid 328, from about amino acid 352 toabout amino acid 357, from about amino acid 539 to about amino acid 544,from about amino acid 555 to about amino acid 560, from about amino acid577 to about amino acid 582, from about amino acid 679 to about aminoacid 684, from about amino acid 682 to about amino acid 687, and fromabout amino acid 763 to about amino acid 768, amidation sites from aboutamino acid 560 to about amino acid 563 and from about amino acid 834 toabout amino acid 837, leucine zipper pattern sequences from about aminoacid 17 to about amino acid 38 and from about amino acid 24 to aboutamino acid 45 and a neutral zinc metallopeptidase, zinc-binding regionsignature sequence from about amino acid 358 to about amino acid 367.Clone DNA73492-1671 has been deposited with ATCC on Oct. 6, 1998 and isassigned ATCC deposit no. 203324.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 180 (SEQ ID NO:317), evidenced significant homologybetween the PRO1563 amino acid sequence and the following Dayhoffsequences: AB014588_(—)1, D67076_(—)1, AB001735_(—)1, P_W47028,AB002364_(—)1, P_W47029, GEN13695, P_R40823, AF005665_(—)1 andDISA_TRIGA.

Example 94 Isolation of cDNA Clones Encoding Human PRO1565

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA67183. Based on an observed homology between theDNA67183 consensus sequence and an EST sequence contained within IncyteEST clone no. 2510320, Incyte EST clone no. 2510320 was purchased andits insert was obtained and sequenced. That insert sequence is shown inFIG. 181 and is herein designated DNA73727-1673 (SEQ ID NO:321).

The entire nucleotide sequence of DNA73727-1673 is shown in FIG. 181(SEQ ID NO:321). Clone DNA73727-1673 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 59-61 and ending at the stop codon at nucleotide positions1010-1012 (FIG. 181). The predicted polypeptide precursor is 317 aminoacids long (FIG. 182). The full-length PRO1565 protein shown in FIG. 182has an estimated molecular weight of about 37,130 daltons and a pI ofabout 5.18. Analysis of the full-length PRO1565 sequence shown in FIG.182 (SEQ ID NO:322) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 40, a potential typeII transmembrane domain from about amino acid 25 to about amino acid 47,potential N-glycosylation sites from about amino acid 94 to about aminoacid 97 and from about amino acid 180 to about amino acid 183,glycosaminoglycan attachment sites from about amino acid 92 to aboutamino acid 95, from about amino acid 70 to about amino acid 73, fromabout amino acid 85 to about amino acid 88, from about amino acid 133 toabout amino acid 136, from about amino acid 148 to about amino acid 151,from about amino acid 192 to about amino acid 195 and from about aminoacid 239 to about amino acid 242, potential N-myristolation sites fromabout amino acid 33 to about amino acid 38, from about amino acid 95 toabout amino acid 100, from about amino acid 116 to about amino acid 121,from about amino acid 215 to about amino acid 220 and from about aminoacid 272 to about amino acid 277, a microbodies C-terminal targetingsignal sequence from about amino acid 315 to about amino acid 317 and acytochrome C family heme-binding site signature sequence from aboutamino acid 9 to about amino acid 14. Clone DNA73727-1673 has beendeposited with ATCC on Nov. 3, 1998 and is assigned ATCC deposit no.203459.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 182 (SEQ ID NO:322), evidenced significant homologybetween the PRO1565 amino acid sequence and the following Dayhoffsequences: AF051425_(—)1, P_R65490, P_R65488, GRPE_STAAU, RNU31330_(—)1,ACCD_BRANA, D50558_(—)1, HUMAMYAB3_(—)1, P_W34452 and P_P50629.

Example 95 Isolation of cDNA Clones Encoding Human PRO1571

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA69559. Based on homology observed between theDNA69559 consensus sequence and an EST sequence contained within theIncyte EST clone no. 3140760, Incyte EST clone no. 3140760 was purchasedand the cDNA insert was obtained and sequenced. The sequence of thiscDNA insert is shown in FIG. 183 and is herein designated asDNA73730-1679.

Clone DNA73730-1679 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 90-92 andending at the stop codon at nucleotide positions 807-809 (FIG. 183). Thepredicted polypeptide precursor is 239 amino acids long (FIG. 184). Thefull-length PRO1571 protein shown in FIG. 184 has an estimated molecularweight of about 25,699 daltons and a pI of about 8.99. Analysis of thefull-length PRO1571 sequence shown in FIG. 184 (SEQ ID NO:324) evidencesthe presence of the following: a signal peptide from about amino acid 1to about amino acid 21 and transmembrane domains from about amino acid82 to about amino acid 103, from about amino acid 115 to about aminoacid 141 and from about amino acid 160 to about amino acid 182. CloneDNA73730-1679 has been deposited with ATCC on Oct. 6, 1998 and isassigned ATCC deposit no. 203320.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 184 (SEQ ID NO:324), evidenced significant homologybetween the PRO1571 amino acid sequence and the following Dayhoffsequences: AF072128_(—)1, AB000712_(—)1, AB000714_(—)1, AF007189_(—)1,AF000959_(—)1, AF068863_(—)1, P_W15288, PM22_HUMAN, P_R30056 andLSU46824_(—)1.

Example 96 Isolation of cDNA Clones Encoding Human PRO1572

Using the method described in Example 1 above, a consensus sequence wasobtained. The consensus sequence is designated herein “DNA69560”. Basedon the DNA69560 consensus sequence and other information providedherein, a clone including another EST (Incyte DNA3051424) from theassembly was purchased and sequenced.

The entire coding sequence of PRO1573 is included in FIG. 185 (SEQ IDNO:325). Clone DNA73734-1680 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 90-92and an apparent stop codon at nucleotide positions 873-875. Thepredicted polypeptide precursor is 261 amino acids long. The signalpeptide is at about amino acids 1-23 and the transmembrane domains areat about amino acids 81-100, 121-141, and 173-194 of SEQ ID NO:326. Oneor more of the transmembrane domains can be deleted or inactivated. Thelocations of a N-glycosylation site, N-myristoylation sites, a tyrosinekinase phosphorylation site and a prokaryotic membrane lipoprotein lipidattachment site are indicated in FIG. 186. Clone DNA73734-1680 has beendeposited with the ATCC and is assigned ATCC deposit no. 203363. Thefull-length PRO1572 protein shown in FIG. 186 has an estimated molecularweight of about 27,856 daltons and a pI of about 8.5.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 186 (SEQ ID NO:326), revealed sequence identity betweenthe PRO1572 amino acid sequence and the following Dayhoff sequences(incorporated herein): AF072127_(—)1, HSU89916_(—)1, AB000713_(—)1,AB000714_(—)1, AB000712_(—)1, AF000959_(—)1, AF072128_(—)1,AF068863_(—)1, P_W29881, and P_W58869.

Example 97 Isolation of cDNA Clones Encoding Human PRO1573

EST 3628990 was identified in an Incyte Database, (LIFESEQ®, IncytePharmaceuticals, Palo Alto, Calif.) and extended in a comparison toother sequences in databases to form an assembly. The alignment searchwas performed using the computer program BLAST or BLAST2 [Altschul etal., Methods in Enzymology, 226: 460-480 (1996)] as a comparison of theECD protein sequences to a 6 frame translation of the EST sequences.Those comparisons resulting in a BLAST score of 70 (or in some cases,90) or greater that did not encode known proteins were clustered andassembled into consensus DNA sequences with the program “phrap” (PhilGreen, University of Washington, Seattle, Wash.). The consensus sequenceis designated herein “DNA69561”.

Based on the DNA69561 consensus sequence and other information providedherein, a clone including another EST (Incyte DNA3752657) from theassembly was purchased and sequenced. This clone came from a breasttumor tissue library.

The entire coding sequence of PRO1573 is included in FIG. 187 (SEQ IDNO:327). Clone DNA73735-1681 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 97-99and an apparent stop codon at nucleotide positions 772-774. Thepredicted polypeptide precursor is 225 amino acids long. The signalpeptide is at about amino acids 1-17 and the transmembrane domains areat about amino acids 82-101, 118-145, and 164-188 of SEQ ID NO:328. Oneor more of the transmembrane domains can be deleted or inactivated. Aphosphorylation site, amidation site, and N-myristoylation sites areshown in FIG. 188. Clone DNA73735-1681 has been deposited with ATCC andis assigned ATCC deposit no. 203356. The full-length PRO1573 proteinshown in FIG. 188 has an estimated molecular weight of about 24,845daltons and a pI of about 9.07.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 188 (SEQ ID NO:328), revealed sequence identity betweenthe PRO1573 amino acid sequence and the following Dayhoff sequences(incorporated herein): AF007189_(—)1, AB000714_(—)1, AB000713_(—)1,AB000712_(—)1. A39484, AF000959_(—)1, AF072127_, AF072128_(—)1,AF068863_(—)1 and AF077739_(—)1.

Example 98 Isolation of cDNA Clones Encoding Human PRO1488

An expressed sequence tag (EST) DNA database (LIFESEQ®, IncytePharmaceuticals, Palo Alto, Calif.) was searched and EST No. 36391121H1was identified as having homology to CPE-R. EST No. 3639112H1 isdesignated herein as “DNA69562”. EST clone 3639112H1, which was derivedfrom a lung tissue library of a 20-week old fetus who died from Patau'ssyndrome, was purchased and the cDNA insert was obtained and sequencedin its entirety. The entire nucleotide sequence of PRO1488 is shown inFIG. 189 (SEQ ID NO:329), and is designated herein as DNA73736-1657.DNA73736-1657 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 6-8 and a stopcodon at nucleotide positions 666-668 (FIG. 189; SEQ ID NO:329). Thepredicted polypeptide precursor is 220 amino acids long.

The full-length PRO1488 protein shown in FIG. 190 has an estimatedmolecular weight of about 23,292 daltons and a pI of about 8.43. Fourtransmembrane domains have been identified as being located at aboutamino acid positions 8-30, 82-102, 121-140, and 166-186.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 190 (SEQ ID NO:330), revealed significant homology betweenthe PRO1488 amino acid sequence and Dayhoff sequence AB000712_(—)1.Homology was also found between the PRO1488 amino acid sequence and thefollowing additional Dayhoff sequences: AB000714_(—)1, AF007189_(—)1,AF000959_(—)1, P_W63697, MMU82758_(—)1, AF072127_(—)1, AF072128_(—)1,HSU89916_(—)1, AF068863_(—)1, CEAF000418_(—)1, and AF077739_(—)1.

Clone DNA73736-1657 was deposited with the ATCC on Nov. 17, 1998, and isassigned ATCC deposit no. 203466.

Example 99 Isolation of cDNA Clones Encoding Human PRO1489

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA69563. Based upon an observed sequence similaritybetween the DNA69563 consensus sequence and an EST sequence containedwithin the Incyte EST clone no. 3376608, Incyte EST clone no. 3376608was purchased and its insert obtained and sequenced. That insert isherein designated DNA73737-1658.

The entire nucleotide sequence of DNA73737-1658 is shown in FIG. 191(SEQ ID NO:331). Clone DNA73737-1658 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 264-266 and ending at the stop codon at nucleotide positions783-785 (FIG. 191). The predicted polypeptide precursor is 173 aminoacids long (FIG. 192). The full-length PRO1489 protein shown in FIG. 192has an estimated molecular weight of about 18,938 daltons and a pI ofabout 9.99. Analysis of the full-length PRO1489 sequence shown in FIG.192 (SEQ ID NO:332) evidences the presence of the following:transmembrane domains from about amino acid 31 to about amino acid 51,from about amino acid 71 to about amino acid 90 and from about aminoacid 112 to about amino acid 133 and a potential N-glycosylation sitefrom about amino acid 161 to about amino acid 164. Clone DNA73737-1658has been deposited with ATCC on Oct. 27, 1998 and is assigned ATCCdeposit no. 203412.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 192 (SEQ ID NO:332), evidenced significant homologybetween the PRO1489 amino acid sequence and the following Dayhoffsequences: AF007189_(—)1, AB000712_(—)1, AF000959_(—)1, MMU82758_(—)1,AF035814_(—)1, AF072127_(—)1, AF072128_(—)1, HSU89916_(—)1,AF068863_(—)1 and PPU50051_(—)1.

Example 100 Isolation of cDNA Clones Encoding Human PRO1474

An expressed sequence tag (EST) DNA database (LIFESEQ®, IncytePharmaceuticals, Palo Alto, Calif.) was searched and an EST wasidentified. This EST showed homology to pancreatic secretory trypsininhibitor.

The clone which included this EST was purchased from Incyte (it camefrom a uterine cervical tissue library) and sequenced in full to revealthe nucleic acid of SEQ ID NO:333, which encodes PRO1474.

The entire nucleotide sequence of PRO1474 is shown in FIG. 193 (SEQ IDNO:333). Clone DNA73739-1645 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 45-47and a stop codon at nucleotide positions 300-302 (FIG. 193; SEQ IDNO:333). The predicted polypeptide precursor is 85 amino acids long. Asindicated in FIG. 194, the Kazal serine protease inhibitor familysignature begins at about amino acid 45 of SEQ ID NO:334. Also indicatedin FIG. 194 is a region conserved in integrin alpha chains (beginning atabout amino acid 32 of SEQ ID NO:334). Clone DNA73739-1645 has beendeposited with the ATCC and is assigned ATCC deposit no. 203270. Thefull-length PRO1474 protein shown in FIG. 194 has an estimated molecularweight of about 9,232 daltons and a pI of about 7.94.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 194 (SEQ ID NO:334), revealed sequence identity betweenthe PRO1474 amino acid sequence and the following Dayhoff sequences (allovomucoids, data incorporated herein by reference): IOVO_FRAER,IOVO_FRAAF, IOVO_FRACO, IOVO_CYRMO, IOVO_STRCA, H61492, C61589,IOVO_POLPL, D61589, and IOVO_TURME.

Example 101 Isolation of cDNA Clones Encoding Human PRO1508

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated Incyte Cluster No. 34523, also referred herein as“DNA10047”. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public and privateEST databases (e.g. GenBank and (LIFESEQ®) to identify existinghomologies. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). The consensussequence obtained therefrom is herein designated “DNA55723”.

In light of the sequence homology between the DNA55723 sequence asequence contained within Incyte EST no. 2989064, the EST clone 2989064was purchased and the cDNA insert was obtained and sequenced in itsentirety. The sequence of this cDNA insert is shown in FIG. 195 and isherein designated as “DNA73742-1662”.

The full length clone shown in FIG. 195 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 70 to 72 and ending at the stop codon found at nucleotidepositions 514 to 516 (FIG. 195; SEQ ID NO:335). The predictedpolypeptide precursor (FIG. 196, SEQ ID NO:335) is 148 amino acids long.Other features of the PRO1508 protein include: a signal sequence atabout amino acids 1-30; a tyrosine kinase phosphorylation motif at aboutamino acids 96-103; and N-myristoylation motifs at about amino acids27-32, 28-33, and 140-145. PRO1508 has a calculated molecular weight ofapproximately 17,183 daltons and an estimated pI of approximately 8.77.Clone DNA73742-1662 was deposited with the ATCC on Oct. 6, 1998 and isassigned ATCC deposit no. 203316.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 196 (SEQ ID NO:336), revealed some homology between thePRO1508 amino acid sequence and the following Dayhoff sequences:HSAJ3728_(—)1; P_R74962; P_R74941; AF053074_(—)1; F69515; S20706;RPB1_PLAFD; A20587_(—)1; A51861_(—)1; and S75947.

Example 102 Isolation of cDNA Clones Encoding Human PRO1555

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated EST cluster no. 521, and also referred to herein as“DNA10316”. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and the LIFESEQ® database to identify existinghomologies. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). The consensussequence obtained therefrom is herein designated “DNA56374”.

In light of the sequence homology between the DNA56374 sequence and anEST sequence contained within Incyte EST no. 2855769, EST no. 2855769was purchased and the cDNA insert was obtained and sequenced. EST no.2855769 was derived from a library constructed from female breast fattissue. The sequence of this cDNA insert is shown in FIG. 197 and isherein designated as DNA73744-1665.

The full length clone shown in FIG. 197 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 90 to 92 and ending at the stop codon found at nucleotidepositions 828 to 830 (FIG. 197; SEQ ID NO:337). The predictedpolypeptide precursor (FIG. 198, SEQ ID NO:338) is 246 amino acids long.PRO1555 has a calculated molecular weight of approximately 26,261daltons and an estimated pI of approximately 5.65. Additional featuresinclude: a signal peptide at about amino acids 1-31; transmembranedomains at about amino acids 11-31 and 195-217; a potentialN-glycosylation site at about amino acids 111-114; potential caseinkinase II phosphorylation sites at about amino acids 2-5, 98-101, and191-194; and potential N-myristoylation sites at about amino acids146-151, and 192-197.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 198 (SEQ ID NO:338), revealed some homology between thePRO1555 amino acid sequence and the following Dayhoff sequences:YKA4_CAEEL, AB014541_(—)1, HVSX99518_(—)2, SSU63019_(—)1, GEN14286,MMU68267_(—)1, XP2_XENLA, ICP4_HSV11, P_W40200, and AE001360_(—)1.

Clone DNA73744-1665 was deposited with the ATCC on Oct. 6, 1998, and isassigned ATCC deposit no. 203322.

Example 103 Isolation of cDNA Clones Encoding Human PRO1485

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein “DNA44791”. Based on the DNA44791 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1485.

PCR primers (2 forward and 2 reverse) were synthesized:

-   forward PCR primer 1: 5′CCCTCCAAGGATGACAAAGGCGC 3′ (SEQ ID NO:341);-   forward PCR primer 2; 5′GGTCAGCAGCTTTCTTGCCCTAAATCAGG 3′ (SEQ ID    NO:342);-   reverse PCR primer 1: 5′ATCTCAGGCGGCATCCTGTCAGCC 3′ (SEQ ID NO:343);    and-   reverse PCR primer 2: 5′GTGGATGCCTGCAAGAAGGTTGGG 3′ (SEQ ID NO:344).

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA44791 sequence which had the followingnucleotide sequence:

-   hybridization probe 5′AGCTTTCTTGCCCTAAATCAGGCCAGCCTCATCAGTCGCTGTGAC    3′ (SEQ ID NO:345)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1485 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human testis.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1485 (designated herein as DNA73746-1654[FIG. 199, SEQ ID NO:339]; and the derived protein sequence for PRO1485.

The entire coding sequence of PRO1485 is shown in FIG. 199 (SEQ IDNO:339). Clone DNA73746-1654 contains a single open reading frame withan apparent translational initiation site at nucleotide positions151-153 and an apparent stop codon at nucleotide positions 595-597 ofSEQ ID NO:339. The predicted polypeptide precursor is 148 amino acidslong. The signal peptide is at about amino acids 1-18 of SEQ ID NO:340.The lysozyme C signature, CAAX box, and an N-gycosylation site are shownin FIG. 200. Clone DNA73746-1654 has been deposited with ATCC and isassigned ATCC deposit no. 203411. The full-length PRO1485 protein shownin FIG. 200 has an estimated molecular weight of about 16,896 daltonsand a pI of about 6.05.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 200 (SEQ ID NO: 340), revealed sequence identity betweenthe PRO1485 amino acid sequence and the following Dayhoff sequences:LYC_PHACO, P_R76684, 2HFL_Y, JC2144, JC5544, JC5555, JC5369, LYC2_PIG,P_R12113, and JC5380.

Example 104 Isolation of cDNA Clones Encoding Human PRO1564

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA67213. Based on the DNA67213 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1564.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (67213.f1) 5′-GGAGAGGTGGTGGCCATGGACAG-3′ (SEQ ID    NO:348)-   reverse PCR primer (67213.r1) 5′-CTGTCACTGCAAGGAGCCAACACC-3′ (SEQ ID    NO:349)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA67213 sequence which had the    following nucleotide sequence-   hybridization probe (67213.p1)    5′-TATGTCGCTGCGAGGTGGTGAAAACCTCGAACTGTCTTTCAAGGC-3′ (SEQ ID NO:350)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1564 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human breast carcinoma tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1564 (designated herein as DNA73760-1672[FIG. 201, SEQ ID NO:346]; and the derived protein sequence for PRO1564.

The entire nucleotide sequence of DNA73760-1672 is shown in FIG. 201(SEQ ID NO:346). Clone DNA73760-1672 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 462-464 and ending at the stop codon at nucleotide positions2379-2381 (FIG. 201). The predicted polypeptide precursor is 639 aminoacids long (FIG. 202). The full-length PRO1564 protein shown in FIG. 202has an estimated molecular weight of about 73,063 daltons and a pI ofabout 6.84. Analysis of the full-length PRO1564 sequence shown in FIG.202 (SEQ ID NO:347) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 28, a transmembranedomain from about amino acid 11 to about amino acid 36, potentialN-glycosylation sites from about amino acid 107 to about amino acid 110and from about amino acid 574 to about amino acid 577, a tyrosine kinasephosphorylation site from about amino acid 50 to about amino acid 57,potential N-myristolation sites from about amino acid 158 to about aminoacid 163, from about amino acid 236 to about amino acid 241, from aboutamino acid 262 to about amino acid 267, from about amino acid 270 toabout amino acid 275, from about amino acid 380 to about amino acid 385and from about amino acid 513 to about amino acid 518, an amidation sitefrom about amino acid 110 to about amino acid 113 and a prokaryoticmembrane lipoprotein lipid attachment site from about amino acid 15 toabout amino acid 25. Clone DNA73760-1672 has been deposited with ATCC onOct. 6, 1998 and is assigned ATCC deposit no. 203314.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 202 (SEQ ID NO:347), evidenced significant homologybetween the PRO1564 amino acid sequence and the following Dayhoffsequences: MMU73819_(—)1, HSY08564_(—)1, P_W34470, P_R66402, PAGT_HUMAN,CEGLY5B_(—)1, CEGLY6A_(—)1, CEGLY6B_(—)1, AP000006_(—)308 and E69322.

Example 105 Isolation of cDNA Clones Encoding Human PRO1755

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated EST Cluster No. 141872. This EST cluster sequencewas then compared to a variety of ESTs from the databases listed aboveto identify existing homologies. The homology search was performed usingthe computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266: 460-480 (1996)). Those comparisons resulting in a BLASTscore of 70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into a consensus DNA sequence withthe program “phrap” (Phil Green, University of Washington, Seattle,Wash.). The consensus sequence obtained therefrom is herein designated“DNA55731”.

In light of the sequence homology between the DNA55731 sequence and asequence contained within Incyte EST no. 257323, the EST clone waspurchased and the cDNA insert was obtained and sequenced. Incyte clone257323 was derived from a library constructed using RNA isolated fromthe hNT2 cell line (Stratagene library no. STR9372310), which wasderived from a human teratocarcinoma that exhibited propertiescharacteristic of a committed neuronal precursor at an early stage ofdevelopment. The sequence of this cDNA insert is shown in FIG. 203 andis herein designated “DNA76396-1698”. Alternatively, the DNA76396-1698sequence can be obtained by preparing oligonucleotide probes and primersand isolating the sequence from an appropriate library (e.g.STR9372310).

The full length clone shown in FIG. 203 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 58 to 60 and ending at the stop codon found at nucleotidepositions 886 to 888 (FIG. 203; SEQ ID NO:351). The predictedpolypeptide precursor (FIG. 204, SEQ ID NO:352) is 276 amino acids long.PRO1755 has a calculated molecular weight of approximately 29,426daltons and an estimated pI of approximately 9.40. Additional featuresinclude: a signal peptide sequence at about amino acids 1-31; atransmembrane domain at about amino acids 178-198; a cAMP andcGMP-dependent protein kinase phosphorylation site at about amino acids210-213; potential N-myristoylation sites at about amino acids 117-122,154-149, and 214-219; and a cell attachment sequence at about aminoacids 149-151.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 204 (SEQ ID NO:352), revealed some homology between thePRO1755 amino acid sequence and the following Dayhoff sequences:APG-BRANA, P_R37743, NAU88587_(—)1, YHL1_EBV, P_W31855, CET10B10_(—)4,AF039404_(—)1, PRP1_HUMAN, AF038575_(—)1, and AF053091_(—)1.

Clone DNA76396-1698 was deposited with the ATCC on Nov. 17, 1998, and isassigned ATCC deposit no. 203471.

Example 106 Isolation of cDNA Clones Encoding Human PRO1757

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of three EST sequences from the Incyte database,designated Incyte EST clones no. 2007947, 2014962 and 1912034. These ESTsequences were then clustered and assembled into a consensus DNAsequence with the program “phrap” (Phil Green, University of Washington,Seattle, Wash.). The consensus sequence obtained therefrom is hereindesignated as DNA56054.

In light of the sequence homology between the DNA56054 sequence and asequence contained within the Incyte EST clone no. 2007947, the IncyteEST clone no. 2007947 was purchased and the cDNA insert was obtained andsequenced. The sequence of this cDNA insert is shown in FIG. 205 and isherein designated as DNA76398-1699.

Clone DNA76398-1699 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 59-61 andending at the stop codon at nucleotide positions 422-424 (FIG. 205). Thepredicted polypeptide precursor is 121 amino acids long (FIG. 206). Thefull-length PRO1757 protein shown in FIG. 206 has an estimated molecularweight of about 12,073 daltons and a pI of about 4.11. Analysis of thefull-length PRO1757 sequence shown in FIG. 206 (SEQ ID NO:354) evidencesthe presence of the following: a signal peptide from about amino acid 1to about amino acid 19, a transmembrane domain from about amino acid 91to about amino acid 110, a glycosaminoglycan attachment site from aboutamino acid 44 to about amino acid 47, a cAMP-and cGMP-dependent proteinkinase phosphorylation site from about amino acid 116 to about aminoacid 119 and a potential N-myristolation site from about amino acid 91to about amino acid 96. Clone DNA76398-1699 has been deposited with ATCCon Nov. 17, 1998 and is assigned ATCC deposit no. 203474.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 206 (SEQ ID NO:354), evidenced significant homologybetween the PRO1757 amino acid sequence and the following Dayhoffsequences: JQ0964, COLL_HSVS7, HSU70136_(—)1, AF003473_(—)1,D89728_(—)1, MTF1_MOUSE, AF029777_(—)1, HSU88153_(—)1 and P_WO5321.

Example 107 Isolation of cDNA Clones Encoding Human PRO1758

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated EST cluster No. 20926. This EST cluster sequencewas then compared to a variety of expressed sequence tag (EST) from thedatabases mentioned above, to identify existing homologies. The homologysearch was performed using the computer program BLAST or BLAST2 (Altshulet al., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA56260.

In light of the sequence homology between the DNA56260 sequence and asequence contained within EST no. 2936330 from the LIFESEQ® database,the EST clone, which originated from a library constructed from thymustissue of a fetus that died from anencephalus, was purchased and thecDNA insert was obtained and sequenced. The sequence of this cDNA insertis shown in FIG. 207 and is herein designated as DNA76399-1700.

The full length clone shown in FIG. 207 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 78 to 80 and ending at the stop codon found at nucleotidepositions 549-551 (FIG. 207; SEQ ID NO:355). The predicted polypeptideprecursor (FIG. 208, SEQ ID NO:356) is 157 amino acids long. PRO1758 hasa calculated molecular weight of approximately 17,681 daltons and anestimated pI of approximately 7.65. Additional features include: asignal peptide from about amino acids 1-15; a potential N-glycosylationsite at about amino acids 24-27; a cAMP- and cGMP-dependent proteinkinase phosphorylation site at about amino acids 27-30; a casein kinaseII phosphorylation site at about amino acids 60-63; potentialN-myristoylation sites at about amino acids 17-22, 50-55, 129-134, and133-138; a cell attachment sequence at about amino acids 153-155; and acytochrome c family heme-binding site signature at about amino acids18-23.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 208 (SEQ ID NO:356), revealed significant homology betweenthe PRO1758 amino acid sequence and Dayhoff sequence no AC005328_(—)2.Homology was also found between the PRO1758 amino acid sequence andDayhoff sequence no. CELC46F2_(—)1.

Clone DNA76399-1700 was deposited with the ATCC on Nov. 17, 1998 and isassigned ATCC deposit no. 203472.

Example 108 Isolation of cDNA Clones Encoding Human PRO1575

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isdesignated herein as “DNA35699”. Based on the DNA35699 consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO1575.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primers: CCAGCAGTGCCCATACTCCATAGC (35699.f1; SEQ ID    NO:359); TGACGAGTGGGATACACTGC (35699.f2; SEQ ID NO:360)-   reverse PCR primer: GCTCTACGGAAACTTCTGCTGTGG (35699.r1; SEQ ID    NO:361)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35699 sequence which had the followingnucleotide sequence:

-   hybridization probe:    ATTCCCAGGCGTGTCATTTGGGATCAGCACTGATTCTGAGGTTCTGACAC (35699.p1; SEQ ID    NO:362)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1575 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human pancreatic tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1575 (designated herein as DNA76401-1683[FIG. 209, SEQ ID NO:357]; and the derived protein sequence for PRO1575.

The entire coding sequence of PRO1575 is shown in FIG. 209 (SEQ IDNO:357). Clone DNA76401-1683 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 22-24and an apparent stop codon at nucleotide positions 841-843. Thepredicted polypeptide precursor is 273 amino acids long. The full-lengthPRO1575 protein shown in FIG. 210 has an estimated molecular weight ofabout 30,480 daltons and a pI of about 4.60. Additional featuresinclude: a signal peptide at about amino acids 1-20; a transmembranedomain at about amino acids 143-162; a potential N-glycosylation site atabout amino acids 100-103; and potential N-myristoylation sites at aboutamino acids 84-89, 103-108, 154-159, and 201-206.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 210 (SEQ ID NO:358), revealed significant homology betweenthe PRO1575 amino acid sequence and Dayhoff sequence A 12005_(—)1.Homology was also revealed between the PRO1575 amino acid sequence andthe following additional Dayhoff sequences: P_P80615; P_R25297;P_R51696; A47300; PDI_DROME; P_R49829; P_R63807; DMALPADAP_(—)1; andDRZNF6_(—)1.

Clone DNA76401-1683 was deposited with the ATCC on Oct. 20, 1998, and isassigned ATCC deposit no. 203360.

Example 109 Isolation of cDNA Clones Encoding Human PRO1787

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap to form an assembly as described in Example 1 above. Thisconsensus sequence is designated herein “DNA45123”. Based on homology ofDNA45123 to Incyte EST 3618549 identified in the assembly, as well asother discoveries and information provided herein, the clone includingthis EST was purchased and sequenced. DNA sequencing of the clone gavethe full-length DNA sequence for PRO1787 and the derived proteinsequence for PRO1787.

The entire coding sequence of PRO1787 is included in FIG. 211 (SEQ IDNO:363). Clone DNA76510-2504 contains a single open reading frame withan apparent translational initiation site at nucleotide positions163-165 and an apparent stop codon at nucleotide positions 970-972 ofSEQ ID NO:363. The approximate locations of the signal peptide,transmembrane domain, N-glycosylation sites, N-myristoylation sites anda kinase phosphorylation site are indicated in FIG. 212. The predictedpolypeptide precursor is 269 amino acids long. Clone DNA76510-2504 hasbeen deposited with the ATCC and is assigned ATCC deposit no. 203477.The full-length PRO1787 protein shown in FIG. 212 has an estimatedmolecular weight of about 29,082 daltons and a pI of about 9.02.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 212 (SEQ ID NO:364), revealed sequence identity betweenthe PRO1787 amino acid sequence and the following Dayhoff sequences:MYP0_RAT, MYP0_HUMAN, MYP0_BOVIN, GEN12838, HSSCN2B2_(—)1,AF007783_(—)1, HSU90716_(—)1, P_W42015, XLU43330_(—)1 and AF060231_(—)1.

Example 110 Isolation of cDNA Clones Encoding Human PRO1781

Initial DNA sequences referred to herein as DNA58070 and DNA56340 wereidentified using a yeast screen, in a human SK-Lu-1 adenocarcinoma cellline cDNA library that preferentially represents the 5′ ends of theprimary cDNA clones. These sequences were clustered and assembled into aconsensus DNA sequence using the computer program “phrap” (Phil Green,University of Washington, Seattle, Wash.). The consensus sequence isdesignated herein as “DNA59575”.

Based on the DNA59575 consensus sequence, the followingoligonucleotides, were synthesized for use as probes to isolate a cloneof the full-length coding sequence for PRO1781 from a human fetal lungcDNA library: TGGAAAAGAAGTCTGGTCAGAAGGTTTAGG (SEQ ID NO:367),CATTTGGCTTCATTCTCCTGCTCTG (SEQ ID NO:368), AAAACCTCAGAACAACTCATTTTGCACC(SEQ ID NO:369) and GTCTCACCATGGTTGCTCTrGCCAAATTGTGGGAAGCAGGG (SEQ IDNO:370).

The full length DNA76522-2500 clone shown in FIG. 213 contained a singleopen reading frame with an apparent translational initiation site atnucleotide positions 21 to 23 and ending at the stop codon found atnucleotide positions 1141-1143 (FIG. 213; SEQ ID NO:365). The predictedpolypeptide precursor (FIG. 214, SEQ ID NO: 366) is 373 amino acidslong. PRO1781 has a calculated molecular weight of approximately 41,221daltons and an estimated pI of approximately 8.54. Additional featuresinclude: a possible signal peptide at about amino acids 1-19; atransmembrane domain at about amino acids 39-60; a tyrosinephosphorylation site at about amino acids 228-236; potentialN-myristoylation sites at about amino acids 1-21, 17-22, 43-48, 45-50,47-52, 49-54, 53-58, 58-63, 59-64, 62-67, 126-131, and 142-147:amidation sites at about amino acids 22-25 and 28-283; and a prokaryoticmembrane lipoprotein lipid attachment site at about amino acids 12-22.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 214 (SEQ ID NO:366), revealed some homology between thePRO1781 amino acid sequence and the following Dayhoff sequences:CEY4510D_(—)5, AP000001_(—)146, P_R10676, DAC_STRSQ, CEC40H5_(—)5,P_R35204, KPU58495_(—)1, KPN16781_(—)1, AF010403_(—)1, andAF056116_(—)14.

Clone DNA76522-2500 was deposited with the ATCC on Nov. 17, 1998, and isassigned ATCC deposit no. 203469.

Example 111 Isolation of cDNA clones Encoding Human PRO1556

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated EST Cluster No. 103158, and also referred to hereinas “DNA10398”. This EST cluster sequence was then compared to a varietyof expressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and the LIFESEQ® database, to identifyexisting homologies. The homology search was performed using thecomputer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology266: 460-480 (1996)). Those comparisons resulting in a BLAST score of 70(or in some cases 90) or greater that did not encode known proteins wereclustered and assembled into a consensus DNA sequence with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.). Theconsensus sequence obtained therefrom is herein designated DNA56417.

In light of the sequence homology between the DNA56417 sequence and asequence contained within Incyte EST no. 959332, EST no. 959332 waspurchased and the cDNA insert was obtained and sequenced. The sequenceof this cDNA insert is shown in FIG. 215 and is herein designated asDNA76529-1666.

The full length clone shown in FIG. 215 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 85 to 87 and ending at the stop codon found at nucleotidepositions 892 to 894 (FIG. 215; SEQ ID NO:371). The predictedpolypeptide precursor (FIG. 216, SEQ ID NO:372) is 269 amino acids long.PRO1556 has a calculated molecular weight of approximately 28,004daltons and an estimated pI of approximately 5.80. Additional featuresinclude: a signal peptide sequence at about amino acids 1-24;transmembrane domains at about amino acids 11-25 and 226-243; apotential N-glycosylation site at about amino acids 182-185, potentialcAMP- and cGMP-dependent protein kinase phosphorylation site at aboutamino acids 70-73; and potential N-myristoylation sites at about aminoacids 29-34, 35-39, 117-122, 121-126, 125-130, 154-159, 166-171,241-246, 246-251, 247-252, 249-254, 250-255, 251-256, 252-257, 253-258,254-259, 255-260, 256-261, 257-262, and 259-264.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 216 (SEQ ID NO:372), revealed some homology between thePRO1556 amino acid sequence and the following Dayhoff sequences:T8F5_(—)4, R23B_MOUSE, CANS_HUMAN, P_W41640, DSU51091_(—)1, TP2B_CHICK,DVU20660_(—)1, S43296, P_R23962, and BRN1_HUMAN.

Clone DNA76529-1666 was deposited with the ATCC on Oct. 6, 1998, and isassigned ATCC deposit no. 203315.

Example 112 Isolation of cDNA Clones Encoding Human PRO1759

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase, designated DNA 10571. This EST cluster sequence was thencompared to a variety of expressed sequence tag (EST) databases whichincluded public EST databases (e.g., GenBank) and a proprietary EST DNAdatabase (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.) toidentify existing homologies. One or more of the ESTs was derived frompooled eosinophils of allergic asthmatic patients. The homology searchwas performed using the computer program BLAST or BLAST2 (Altshul etal., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated DNA57313.

In light of the sequence homology between the DNA57313 sequence and theIncyte EST 2434255, the clone including this EST was purchased and thecDNA insert was obtained and sequenced. The sequence of this cDNA insertis shown in FIG. 217 and is herein designated as DNA76531-1701.

The full length clone shown in FIG. 217 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 125-127 and ending at the stop codon found at nucleotidepositions 1475-1477 (FIG. 217; SEQ ID NO:373). The approximate locationsof the signal peptide and transmembrane domains are indicated in FIG.218, whereas the approximate locations for N-myristoylation sites, alipid attachment site, an amidation site and a kinase phosphorylationsite are indicated in FIG. 218. The predicted polypeptide precursor(FIG. 218, SEQ ID NO:374) is 450 amino acids long. PRO1759 has acalculated molecular weight of approximately 49,765 daltons and anestimated pI of approximately 8.14. Clone DNA76531-1701 was depositedwith the ATCC on Nov. 17, 1998 and is assigned ATCC deposit no. 203465.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 218 (SEQ ID NO:374), revealed sequence identity betweenthe PRO1759 amino acid sequence and the following Dayhoff sequences:OPDE_PSEAE, TH11_TRYBB, S67684, RGT2_YEAST, S68362, ATSUGTRPR_(—)1,P_W17836 (Patent application WO9715668-A2), F69587, A48076, and A45611.

Example 113 Isolation of cDNA Clones Encoding Human PRO1760

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the Incytedatabase. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. One or more of the ESTs was derived from a prostate tumorlibrary. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). The consensussequence obtained therefrom is herein designated DNA58798.

In light of the sequence homology between DNA58798 sequence and theIncyte EST 3358745, the clone including this EST was purchased and thecDNA insert was obtained and sequenced. The sequence of this cDNA insertis shown in FIG. 219 and is herein designated as DNA76532-1702.

The full length clone shown in FIG. 219 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 60-62 and ending at the stop codon found at nucleotidepositions 624-626 (FIG. 219; SEQ ID NO:375). The predicted polypeptideprecursor (FIG. 220, SEQ ID NO:376) is 188 amino acids long. Motifs arefurther indicated in FIG. 220. PRO1760 has a calculated molecular weightof approximately 21,042 daltons and an estimated pI of approximately5.36. Clone DNA76532-1702 was deposited with the ATCC on Nov. 17, 1998and is assigned ATCC deposit no. 203473.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 220 (SEQ ID NO:376), revealed sequence identity betweenthe PRO1760 amino acid sequence and the following Dayhoff sequences:CELT07F12_(—)2, T22J18_(—)16, ATF1C12_(—)3, APE3_YEAST, P_W22471,SAU56908_(—)1, SCPA_STRPY, ATAC00423817, SAPURCLUS_(—)2 andAF041468_(—)9.

Example 114 Isolation of cDNA Clones Encoding Human PRO1561

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap and repeated cycles of BLAST and phrap to extend a sequenceas far as possible using the EST sequences discussed above as describedin Example 1 above. This consensus sequence is herein designatedDNA40630. Based on the DNA40630 consensus sequence, oligonucleotideswere synthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate a clone ofthe full-length coding sequence for PRO1561.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (40630.f1) 5′-CTGCCTCCACTGCTCTGTGCTGGG-3′ (SEQ ID    NO:379)-   reverse PCR primer (40630.r1) 5′-CAGAGCAGTGGATGTTCCCCTGGG-3′ (SEQ ID    NO:380)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA40630 sequence which had the    following nucleotide sequence-   hybridization probe (40630.p1)    5′-CTGAACAAGATGGTCAAGCAAGTGACTGGGAAAATGCCCATCCTC-3′ (SEQ ID NO:381)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1561 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human breast tumor tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1561 (designated herein as DNA76538-1670[FIG. 221, SEQ ID NO:377]; and the derived protein sequence for PRO1561.

The entire nucleotide sequence of DNA76538-1670 is shown in FIG. 221(SEQ ID NO:377). Clone DNA76538-1670 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 29-31 and ending at the stop codon at nucleotide positions377-379 (FIG. 221). The predicted polypeptide precursor is 116 aminoacids long (FIG. 222). The full-length PRO1561 protein shown in FIG. 222has an estimated molecular weight of about 12,910daltons and a pI ofabout 6.41. Analysis of the full-length PRO1561 sequence shown in FIG.222 (SEQ ID NO:378) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 17, a transmembranedomain from about amino acid 1 to about amino acid 24, a potentialN-glycosylation site from about amino acid 86 to about amino acid 89,potential N-myristolation sites from about amino acid 20 to about aminoacid 25 and from about amino acid 45 to about amino acid 50 and aphospholipase A2 histidine active site from about amino acid 63 to aboutamino acid 70. Clone DNA76538-1670 has been deposited with ATCC on Oct.6, 1998 and is assigned ATCC deposit no. 203313.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 222 (SEQ ID NO:378), evidenced significant homologybetween the PRO1561 amino acid sequence and the following Dayhoffsequences: P_R63053, P_R25416, P_R63055, P_P93363, P_R63046, PA2A_VIPAA,P_W58476, GEN13747, PA2X_HUMAN and PA2A_CRODU.

In addition to the above, a sequence homology search evidencedsignificant homology between the DNA40630 consensus sequence and IncyteEST clone no. 1921092. As such, Incyte EST clone no. 1921092 waspurchased and the insert obtained and sequenced, thereby giving rise tothe DNA76538-1670 sequence shown in FIG. 221 (SEQ ID NO:377).

Example 115 Isolation of cDNA Clones Encoding Human PRO1567

A cDNA sequence isolated in the amylase screen described in Example 2above is herein designated DNA47580. The DNA47580 sequence was thencompared to a variety of expressed sequence tag (EST) databases whichincluded public EST databases (e.g., GenBank) and a proprietary EST DNAdatabase (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.) toidentify existing homologies. The homology search was performed usingthe computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266: 460-480 (1996)). Those comparisons resulting in a BLASTscore of 70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into consensus DNA sequences withthe program “phrap” (Phil Green, University of Washington, Seattle,Wash.). The consensus sequence obtained therefrom is herein designated“DNA57246”.

In light of the sequence homology between the DNA57246 sequence and ESTno. 1793996 from the LIFESEQ™ database, the clone containing the EST no.1793996, which originates from a library constructed from prostate tumortissue, was purchased and the cDNA insert was obtained and sequenced.The sequence of this cDNA insert is shown in FIG. 223 (SEQ ID NO:382)and is herein designated as DNA76541-1675.

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 109-111, and a stop signal at nucleotide positions 643-645(FIG. 223; SEQ ID NO:382). The predicted polypeptide precursor is 178amino acids long has a calculated molecular weight of approximately19,600 daltons and an estimated pI of approximately 5.89. Additionalfeatures include a signal peptide at about amino acids 1-22; a potentialN-glycosylation site at about amino acids 167-170; a protein kinase Cphosphorylation site at about amino acids 107-109; and potentialN-myristoylation sites at about amino acids 46-51, 72-77, and 120-125.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 224 (SEQ ID NO:383), evidenced significant homologybetween the PRO1567 amino acid sequence and human colon specific geneCSG6 polypeptide designated Dayhoff sequence “P_W06549”. Homology wasalso found between the PRO1567 amino acid sequence and the followingadditional Dayhoff sequences: HUAC002301_(—)1, P_(—)246880, A49685,SPBP_RAT, S42924, SPBP_MOUSE, 152115, MMU03711_(—)1, and AF041468_(—)31.

Clone DNA76541-1675 has been deposited with the ATCC on Oct. 27, 1998,and is assigned ATCC deposit no. 203409.

Example 116 Isolation of cDNA Clones Encoding Human PRO1693

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA38251. Based on the DNA38251 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1693.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (38251.f1) 5′-CTGGGATCTGAACAGTTTCGGGGC-3′ (SEQ ID    NO:386)-   reverse PCR primer (38251.r1) 5′-GGTCCCCAGGACATGGTCTGTCCC-3′ (SEQ ID    NO:387)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA38251 sequence which had the    following nucleotide sequence-   hybridization probe (38251.p1)    5′-GCTGAGTTTACATTTACGGTCTAACTCCCTGAGAACCATCCCTGTGCG-3′ (SEQ ID    NO:388)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1693 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1693 (designated herein as DNA77301-1708[FIG. 225, SEQ ID NO:384]; and the derived protein sequence for PRO1693.

The entire nucleotide sequence of DNA77301-1708 is shown in FIG. 225(SEQ ID NO:384). Clone DNA77301-1708 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 508-510 and ending at the stop codon at nucleotide positions2047-2049 (FIG. 225). The predicted polypeptide precursor is 513 aminoacids long (FIG. 226). The full-length PRO1693 protein shown in FIG. 226has an estimated molecular weight of about 58,266 daltons and a pI ofabout 9.84. Analysis of the full-length PRO1693 sequence shown in FIG.226 (SEQ ID NO:385) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 33, a transmembranedomain from about amino acid 420 to about amino acid 442, potentialN-glycosylation sites from about amino acid 126 to about amino acid 129,from about amino acid 357 to about amino acid 360, from about amino acid496 to about amino acid 499 and from about amino acid 504 to about aminoacid 507, a cAMP-and cGMP-dependent protein kinase phosphorylation sitefrom about amino acid 465 to about amino acid 468, a tyrosine kinasephosphorylation site from about amino acid 136 to about amino acid 142and potential N-myristolation sites from about amino acid 11 to aboutamino acid 16, from about amino acid 33 to about amino acid 38, fromabout amino acid 245 to about amino acid 250, from about amino acid 332to about amino acid 337, from about amino acid 497 to about amino acid502 and from about amino acid 507 to about amino acid 512. CloneDNA77301-1708 has been deposited with ATCC on Oct. 27, 1998 and isassigned ATCC deposit no. 203407.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 226 (SEQ ID NO:385), evidenced significant homologybetween the PRO1693 amino acid sequence and the following Dayhoffsequences: AB007876_(—)1, ALS_MOUSE, HSCHON03_(—)1, P_R85889,AF062006_(—)1, AB014462_(—)1, A58532, MUSLRRPA_(—)1, AB007865_(—)1 andAF030435_(—)1.

Example 117 Isolation of cDNA Clones Encoding Human PRO1784

A cDNA sequence isolated in the amylase screen described in Example 2above is herein designated DNA43862. Based on the DNA43862 sequence,oligonucleotide probes were generated and used to screen a human fetalkidney library prepared as described in paragraph 1 above. The cloningvector was pRK5B (pRK5B is a precursor of pRK5D that does not containthe SfiI site; see, Holmes et al., Science, 253: 1278-1280 (1991)), andthe cDNA size cut was less than 2800 bp.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (f1) 5′-CTTTTCAGTGTCACCTCAGCGATCTC-3′ (SEQ ID    NO:391); and-   reverse PCR primer (r1) 5′-CCAAAACATGGAGCAGGAACAGG-3′ (SEQ ID    NO:392).    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the DNA43862 sequence which had the following    nucleotide sequence:-   hybridization probe (p1)    5′-CCAGTTGGTGCTCTCGGACCTACCATGCGAAGAAGATGAAATGTGTG-3′ (SEQ ID    NO:393).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1784 gene using the probe oligonucleotideand one of the PCR primers.

A full length clone was identified that contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 68-70, and a stop signal at nucleotide positions 506-508 (FIG.227; SEQ ID NO:389). The predicted polypeptide precursor is 146 aminoacids long has a calculated molecular weight of approximately 16,116daltons and an estimated pI of approximately 4.99. The approximatelocations of the signal peptide, transmembrane domain andN-myristoylation site are indicated in FIG. 228. Clone DNA77303-2502 hasbeen deposited with the ATCC and is assigned ATCC deposit no. 203479.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 228 (SEQ ID NO:390), evidenced sequence identity betweenthe PRO1784 amino acid sequence and the following Dayhoff sequences:RNU87224_(—)1, RNAF000114_(—)1, P_W31947, S18038, AE001300_(—)8,AF039833_(—)1, P_W39833_(—)1, P_W39788, HSU87223_(—)1, NTU06712_(—)1,and P_W31946.

Example 118 Isolation of cDNA Clones Encoding Human PRO1605

A cDNA clone (DNA77648-1688) encoding a native human PRO1605 polypeptidewas identified by a yeast screen, in a human fetal kidney cDNA librarythat preferentially represents the 5′ ends of the primary cDNA clones.

The full-length DNA77648-1688 clone shown in FIG. 229 contains a singleopen reading frame with an apparent translational initiation site atnucleotide positions 425-427 and ending at the stop codon at nucleotidepositions 845-847 (FIG. 229). The predicted polypeptide precursor is 140amino acids long (FIG. 230). The full-length PRO1605 protein shown inFIG. 230 has an estimated molecular weight of about 15,668 daltons and apI of about 10.14. Analysis of the full-length PRO1605 sequence shown inFIG. 230 (SEQ ID NO:395) evidences the presence of the following: asignal peptide from about amino acid 1 to about amino acid 26. CloneDNA77648-1688 has been deposited with ATCC on Oct. 27, 1998 and isassigned ATCC deposit no. 203408.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 230 (SEQ ID NO:395), evidenced significant homologybetween the PRO1605 amino acid sequence and the following Dayhoffsequences: GNT5_HUMAN, P_R48975, P_W22519, MM26SPROT_(—)1,HSU86782_(—)1. CH60_LEPIN, HMCT_HELPY, F65126, HIU08875_(—)1 andP_R41724.

Example 119 Isolation of cDNA Clones Encoding Human PRO1788

The extracellular domain (ECD) sequences (including the secretion signalsequence, if any) from about 950 known secreted proteins from theSwiss-Prot public database were used to search EST databases. The ESTdatabases included public EST databases (e.g., GenBank), and aproprietary EST database (LIFESEQ®, Incyte Pharmaceuticals, Palo Alto,Calif.). The search was performed using the computer program BLAST orBLAST2 [Altschul et al., Methods in Enzymology, 266: 460-480 (1996)] asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Incyte Clone No. 2968304 was identified as a sequenceof interest having a BLAST score of 70 or greater that did not encodeknown proteins. The nucleotide sequence of Incyte Clone No. 2968304 isdesignated herein as “DNA6612”.

In addition, the DNA6612 sequence was extended using repeated cycles ofBLAST and phrap (Phil Green, University of Washington, Seattle, Wash.)to extend the sequence as far as possible using the sources of ESTsequences discussed above. The extended consensus sequence is designatedherein as “DNA49648”. Based on the DNA49648 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1788.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer: CCCTGCCAGCCGAGAGCTTCACC (49648.f1; SEQ ID    NO:398)-   reverse PCR primer: GGTTGGTGCCCGAAAGGTCCAGC (49648.r1; SEQ ID    NO:399)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA49648 sequence which had the followingnucleotide sequence:

-   hybridization probe: CAACCCCAAGCTTAACTGGGCAGGAGCTGAGGTG TTTTCAGGCC    (49648.p 1; SEQ ID NO:400)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1788 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1788 (designated herein as DNA77652-2505[FIG. 231, SEQ ID NO:396]; and the derived protein sequence for PRO1788.

The entire coding sequence of PRO1788 is shown in FIG. 231 (SEQ IDNO:396). Clone DNA77652-2505 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 64-66and an apparent stop codon at nucleotide positions 1123-1125. Thepredicted polypeptide precursor is 353 amino acids long. The full-lengthPRO1788 protein shown in FIG. 232 has an estimated molecular weight ofabout 37,847 daltons and a pl of about 6.80. Additional features ofPRO1788 include: a signal peptide at about amino acids 1-16;transmembrane domains at about amino acids 215-232 and 287-304;potential N-glycosylation sites at about amino acids 74-77 and 137-140;a glycosaminoglycan attachment site at about amino acids 45-48; atyrosine kinase phosphorylation site at about amino acids 318-325;N-myristoylation sites at about amino acids 13-18, 32-37, 88-93,214-219, and 223-228; and a leucine zipper pattern at about amino acids284-305.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 232 (SEQ ID NO:397), revealed significant homology betweenthe PRO1788 amino acid sequence and the following Dayhoff sequences:AF030435_(—)1; AF062006_(—)1; DMTARTAN_(—)1; GARP_HUMAN; S42799;P_R71294; HSU88879_(—)1; DROWHEELER_(—)1; A58532; and AF068920_(—)1.

Clone DNA77652-2505 was deposited with the ATCC on Nov. 17, 1998, and isassigned ATCC deposit no. 203480.

Example 120 Isolation of cDNA Clones Encoding Human PRO1801

A proprietary expressed sequence tag (EST) DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST wasidentified which showed homology to the IL-19 protein. This EST sequenceis Incyte EST clone no. 819592 and is herein designated DNA79293. Basedon the DNA79293 sequence, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence of interest,and 2) for use as probes to isolate a clone of the full-length codingsequence for PRO1801.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′-CTCCTGTGGTCTCCAGATTTCAGGCCTA-3′ (SEQ ID    NO:403)-   reverse PCR primer 5′-AGTCCTCCTTAAGATTCTGATGTCAA-3′ (SEQ ID NO:404)

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue. The cDNA libraries used to isolated the cDNA clones wereconstructed by standard methods using commercially available reagentssuch as those from Invitrogen, San Diego, Calif. The cDNA was primedwith oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1801 (designated herein as DNA83500-2506[FIG. 233, SEQ ID NO:401]; and the derived protein sequence for PRO1801.

The entire nucleotide sequence of DNA83500-2506 is shown in FIG. 233(SEQ ID NO:401). Clone DNA83500-2506 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 109-111 and ending at the stop codon at nucleotide positions892-894 (FIG. 233). The predicted polypeptide precursor is 261 aminoacids long (FIG. 234). The full-length PRO1801 protein shown in FIG. 234has an estimated molecular weight of about 29,667 daltons and a pI ofabout 8.76. Analysis of the full-length PRO1801 sequence shown in FIG.234 (SEQ ID NO:402) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 42, cAMP- andcGMP-dependent protein kinase phosphorylation sites from about aminoacid 192 to about amino acid 195 and from about amino acid 225 to aboutamino acid 228 and potential N-myristolation sites from about amino acid42 to about amino acid 47, from about amino acid 46 to about amino acid51 and from about amino acid 136 to about amino acid 141. CloneDNA83500-2506 has been deposited with ATCC on Oct. 29, 1998 and isassigned ATCC deposit no. 203391.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 234 (SEQ ID NO:402), evidenced significant homologybetween the PRO1801 amino acid sequence and the following Dayhoffsequences: P_W37935, HGS_B477, P_R32277, IL10_MACFA, P_W46585, P_R39714,P_R71471, P_R10159, IL10_RAT and P_W57201.

Example 121 Isolation of cDNA Clones Encoding Human UCP4

EST databases, which included public EST databases (e.g., GenBank), anda proprietary EST database (LIFESEQ™, Incyte Pharmaceuticals, Palo Alto,Calif.), were searched for sequences having homologies to human UCP3.The search was performed using the computer program BLAST or BLAST2[Altschul et al., Methods in Enzymology, 266: 460-480 (1996)] as acomparison of the UCP3 protein sequences to a 6 frame translation of theEST sequences. Those comparisons resulting in a BLAST score of 70 (or insome cases, 90) or greater that did not encode known proteins wereclustered and assembled into consensus DNA sequences with the programAssemblLIGN and MacVector (Oxford Molecular Group, Inc.).

A DNA sequence (“fromDNA”) was assembled relative to other EST sequencesusing AssemblLIGN software. In addition, the from DNA sequence wasextended using repeated cycles of BLAST and AssemblLIGN to extend thesequence as far as possible using the sources of EST sequences discussedabove. Based on this DNA sequence, oligonucleotides were synthesized toisolate a clone of the full-length coding sequences for UCP4 by PCR.Forward and reverse PCR primers generally range from 20 to 30nucleotides and are often designed to give a PCR product of about100-1000 bp in length. The probe sequences are typically 40-55 bp inlength. In some cases, additional oligonucleotides are synthesized whenthe consensus sequence is greater than about 1-1.5 kbp. PCR primers(forward and reverse) were synthesized:

-   forward PCR primer CGCGGATCCCGTTATCGTCTTGCGCTACTGC (SEQ ID NO:407)-   reverse PCR primer GCGGAATTCTTAAAATGGACTGACTCCACTCATC (SEQ ID    NO:408)

RNA for construction of the cDNA libraries was isolated from braintissue. The cDNA libraries used to isolated the cDNA clones wereconstructed by standard methods using commercially available reagentssuch as those from Invitrogen, San Diego, Calif. The cDNA was primedwith oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

DNA sequencing of the clone isolated by PCR as described above gave thefull-length DNA sequence for UCP4 (designated herein as DNA77568-1626[FIG. 235, SEQ ID NO:405] and the derived protein sequence for UCP4.

The entire coding sequence of UCP4 is shown in FIG. 235 (SEQ ID NO:405).Clone DNA77568-1626 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 27-29,and an apparent stop codon at nucleotide positions 996-998. (See FIG.235; SEQ ID NO:405). The predicted polypeptide precursor is 323 aminoacids long. It is presently believed that UCP4 is a membrane-boundprotein and contains at least 6 transmembrane regions. These putativetransmembrane regions in the UCP4 amino acid sequence are illustrated inFIG. 236. Clone DNA77568-1626, contained in the pcDNA3 vector(Invitrogen) has been deposited with ATCC and is assigned ATCC depositno. 203134. UCP4 polypeptide is obtained or obtainable by expressing themolecule encoded by the cDNA insert of the deposited ATCC 203134 vector.Digestion of the vector with BamHI and EcoRI restriction enzymes willyield an approximate 972 plus 34 bp insert. The full-length UCP4 proteinshown in FIG. 236 has an estimated molecular weight of about 36,061daltons and a pI of about 9.28.

Example 122 Isolation of cDNA Clones Encoding Human PRO193

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. Based on this consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence for PRO193.

A pair of PCR primers (forward and reverse) were synthesized:

-   forward PCR primer 5′-GTTTGAGGAAGCTGGGATAC-3′ (SEQ ID NO:411); and-   reverse PCR primer 5′-CCAAACTCGAGCACCTGTTC-3′ (SEQ ID NO:412).    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus sequence which had the following    nucleotide sequence:-   hybridization probe 5′-ATGGCAGGCTCCTAGATAATTTTCGTTGGCCAGAATGTG-3′    (SEQ ID NO:413).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO193 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human retina tissue (LIB94).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO193 [herein designated as DNA23322-1393](SEQ ID NO:409) and the derived protein sequence for PRO193.

The entire nucleotide sequence of DNA23322-1393 is shown in FIG. 237(SEQ ID NO:409). Clone DNA23322-1393 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 138-140 and ending at the stop codon at nucleotide positions612-614 (FIG. 237). The predicted polypeptide precursor is 158 aminoacids long (FIG. 238). The full-length PRO193 protein shown in FIG. 238has an estimated molecular weight of about 17,936 and a pI of about5.32. Clone DNA23322-1393 has been deposited with the ATCC. Regardingthe sequence, it is understood that the deposited clone contains thecorrect sequence, and the sequences provided herein are based on knownsequencing techniques.

Still analyzing the amino acid sequence of SEQ ID NO:410, transmembranedomains are at about amino acids 23-42, 60-80, 97-117 and 128-148 of SEQID NO:410. A cell attachment sequence is at about amino acids 81-83 ofSEQ ID NO:410. A peroxidase proximal heme-ligand domain is at aboutamino acids 81-83 of SEQ ID NO:410. The corresponding nucleotides can beroutinely determined given the sequences provided herein.

Example 123 Isolation of cDNA Clones Encoding Human PRO1130

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA34360. Based on the DNA34360 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1130.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (34360.f1) 5′-GCCATAGTCACGACATGGATG-3′ (SEQ ID    NO:416)-   forward PCR primer (34360.f2) 5′-GGATGGCCAGAGCTGCTG-3′ (SEQ ID    NO:417)-   forward PCR primer (34360.f3) 5′-AAAGTACAAGTGTGGCCTCATCAAGC-3′ (SEQ    ID NO:418)-   reverse PCR primer (34360.r1) 5′-TCTGACTCCTAAGTCAGGCAGGAG-3′ (SEQ ID    NO:419)-   reverse PCR primer (34360.r2) 5′-ATTCTCTCCACAGACAGCTGGTTC′3′ (SEQ ID    NO:420)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA34360 sequence which had the    following nucleotide sequence-   hybridization probe (34360.p1)    5′-GTACAAGTGTGGCCTCATCAAGCCCTGCCCAGCCAACTACTTTGCG-3′ (SEQ ID NO:421)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1130 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human aortic endothelial cell tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1130 (designated herein as DNAS9814-1486[FIG. 239, SEQ ID NO:414]; and the derived protein sequence for PRO1130.

The entire nucleotide sequence of DNA59814-1486 is shown in FIG. 239(SEQ ID NO:414). Clone DNA59814-1486 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 312-314 and ending at the stop codon at nucleotide positions984-986 (FIG. 239). The predicted polypeptide precursor is 224 aminoacids long (FIG. 240). The full-length PRO1130 protein shown in FIG. 240has an estimated molecular weight of about 24,963 daltons and a pI ofabout 9.64. Analysis of the full-length PRO1130 sequence shown in FIG.240 (SEQ ID NO:415) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 15, anATP/GTP-binding site motif A from about amino acid 184 to about aminoacid 191 and a potential N-glycosylation site from about amino acid 107to about amino acid 110. Clone DNA59814-1486 has been deposited withATCC on Oct. 20, 1998 and is assigned ATCC deposit no. 203359.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 240 (SEQ ID NO:415), evidenced significant homologybetween the PRO1130 amino acid sequence and the following Dayhoffsequences: P_WO6547, 216_HUMAN, D87120_(—)1, MMU72677_(—)1,LAU04889_(—)1, and D69319.

Example 124 Isolation of cDNA Clones Encoding Human PRO1335

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35727. Based on the DNA35727 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO1335.

PCR primers (forward and reverse) were synthesized:

-   forward PCR primer (35727.f1) 5′-GTAAAGTCGCTGGCCAGC-3′ (SEQ ID    NO:424)-   forward PCR primer (35727.f2) 5′-CCCGATCTGCCTGCTGTA-3′ (SEQ ID    NO:425)-   reverse PCR primer (35727.r1) 5′-CTGCACTGTATGGCCATTATTGTG-3′ (SEQ ID    NO:426)    Additionally, a synthetic oligonucleotide hybridization probe was    constructed from the consensus DNA35727 sequence which had the    following nucleotide sequence-   hybridization probe (35727-p1)    5′-CAGAAACCCATGATACCCTACTGAACACCGAATCCCCTGGAAGCC-3′ (SEQ ID NO:427)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO1335 gene using the probe oligonucleotideand one of the PCR primers. RNA for construction of the cDNA librarieswas isolated from human retina tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO1335 (designated herein as DNA62812-1594[FIG. 241, SEQ ID NO:422]; and the derived protein sequence for PRO1335.

The entire nucleotide sequence of DNA62812-1594 is shown in FIG. 241(SEQ ID NO:422). Clone DNA62812-1594 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 271-273 and ending at the stop codon at nucleotide positions1282-1284 (FIG. 241). The predicted polypeptide precursor is 337 aminoacids long (FIG. 242). The full-length PRO1335 protein shown in FIG. 242has an estimated molecular weight of about 37,668 daltons and a pI ofabout 6.27. Analysis of the full-length PRO1335 sequence shown in FIG.242 (SEQ ID NO:423) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 15, a transmembranedomain from about amino acid 291 to about amino acid 310, a potentialN-glycosylation site from about amino acid 213 to about amino acid 216and amino acid sequence blocks having homology to eukaryotic-typecarbonic anhydrase proteins from about amino acid 197 to about aminoacid 245, from about amino acid 104 to about amino acid 140 and fromabout amino acid 22 to about amino acid 69. Clone DNA62812-1594 has beendeposited with ATCC on Sep. 9, 1998 and is assigned ATCC deposit no.203248.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 242 (SEQ ID NO:423), evidenced significant homologybetween the PRO1335 amino acid sequence and the following Dayhoffsequences: AF037335_(—)1, I38013, PTPG_MOUSE, CAH2_HUMAN, 1CAC,CAH7_HUMAN, CAH3_HUMAN, CAH1_HUMAN, CAH5_HUMAN and P_R41746.

Example 125 Isolation of cDNA Clones Encoding Human PRO1329

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST cluster sequence from the LIFESEQ®database, designated Incyte Cluster No. 167544, also referred herein as“DNA10680”. This EST cluster sequence was then compared to a variety ofexpressed sequence tag (EST) databases which included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ®,Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existinghomologies. The homology search was performed using the computer programBLAST or BLAST2 (Altshul et al., Methods in Enzymology 266: 460-480(1996)). Those comparisons resulting in a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into a consensus DNA sequence with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.). One or more ofthe ESTs was derived from a cDNA library constructed from RNA isolatedfrom synovial membrane tissue removed from the elbow of a female withrheumatoid arthritis. The consensus sequence obtained therefrom isherein designated “DNA58836”.

In light of the sequence homology between the DNA58836 sequence and asequence contained within the Incyte EST clone no. 368774, EST clone368774 was purchased and the cDNA insert was obtained and sequenced. Thesequence of this cDNA insert is shown in FIG. 243 and is hereindesignated as DNA66660-1585.

The full length clone shown in FIG. 243 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 90 to 92 and ending at the stop codon found at nucleotidepositions 717 to 719 (FIG. 243; SEQ ID NO:428). The predictedpolypeptide precursor (FIG. 244, SEQ ID NO:429) is 209 amino acids long,with a signal sequence at about amino acids 1-16. PRO1329 has acalculated molecular weight of approximately 21,588 daltons and anestimated pI of approximately 5.50. Clone DNA66660-1585 was depositedwith the ATCC on Sep. 22, 1998 and is assigned ATCC deposit no. 203279.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 244 (SEQ ID NO:429), revealed some homology between thePRO1329 amino acid sequence and the following Dayhoff sequences:CELK06A9_(—)3, PROA_XANCP. CXU21300_(—)4. MTV037_(—)17, SYN1_RAT,I56542, S60743, BNOLE3_(—)1, AB001573_(—)1, and P_P80671.

Example 126 Isolation of cDNA Clones Encoding Human PRO1550

Use of the signal sequence algorithm described in Example 3 aboveallowed identification of an EST sequence from the Merck database,designated CELT15B7_(—)12, also referred herein as “DNA 10022”. This ESTsequence was then compared to a variety of expressed sequence tag (EST)databases which included public and proprietary EST databases (e.g.,GenBank and LIFESEQ® to identify existing homologies. The homologysearch was performed using the computer program BLAST or BLAST2 (Altshulet al., Methods in Enzymology 266: 460-480 (1996)). Those comparisonsresulting in a BLAST score of 70 (or in some cases 90) or greater thatdid not encode known proteins were clustered and assembled into aconsensus DNA sequence with the program “phrap” (Phil Green, Universityof Washington, Seattle, Wash.). The consensus sequence obtainedtherefrom is herein designated “DNA55708”.

In light of the sequence homology between the DNA55708 sequence and asequence contained within Incyte EST no. 3411659, the EST clone 3411659was purchased and the cDNA insert was obtained and sequenced in itsentirety. The sequence of this cDNA insert is shown in FIG. 245 and isherein designated as “DNA76393-1664”.

The full length clone shown in FIG. 245 contained a single open readingframe with an apparent translational initiation site at nucleotidepositions 138 to 140 and ending at the stop codon found at nucleotidepositions 867 to 869 (FIG. 245; SEQ ID NO:430). The predictedpolypeptide precursor (FIG. 246, SEQ ID NO:431) is 243 amino acids long.Other features of the PRO1550 protein include: a signal sequence atabout amino acids 1-30; a hydrophobic domain at about amino acids195-217; and a potential N-glycosylation site at about amino acids186-189. PRO1550 has a calculated molecular weight of approximately26,266 daltons and an estimated pI of approximately 8.43. CloneDNA76393-1664 was deposited with the ATCC on Oct. 6, 1998, and isassigned ATCC deposit no. 203323.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 246 (SEQ ID NO:431), revealed some homology between thePRO1550 amino acid sequence and the following Dayhoff sequences:CELF59E12_(—)11; CA24_ASCSU; AF018082_(—)1; CA13_BOVIN; CA54_HUMAN;CA34_HUMAN; HUMCOL7A1X_(—)1; P_WO9643; AF053538_(—)1; andHSEMCXIV2_(—)1.

Example 127 Use of PRO as a Hybridization Probe

The following method describes use of a nucleotide sequence encoding PROas a hybridization probe.

DNA comprising the coding sequence of full-length or mature PRO asdisclosed herein is employed as a probe to screen for homologous DNAs(such as those encoding naturally-occurring variants of PRO) in humantissue cDNA libraries or human tissue genomic libraries.

Hybridization and washing of filters containing either library DNAs isperformed under the following high stringency conditions. Hybridizationof radiolabeled PRO-derived probe to the filters is performed in asolution of 50% formamide, 5×SSC, 0.1% SDS, 0.1% sodium pyrophosphate,50 mM sodium phosphate, pH 6.8, 2× Denhardt's solution, and 10% dextransulfate at 42° C. for 20 hours. Washing of the filters is performed inan aqueous solution of 0.1×SSC and 0.1% SDS at 42° C.

DNAs having a desired sequence identity with the DNA encodingfull-length native sequence PRO can then be-identified using standardtechniques known in the art.

Example 128 Expression of PRO in E. coli

This example illustrates preparation of an unglycosylated form of PRO byrecombinant expression in E. coli.

The DNA sequence encoding PRO is initially amplified using selected PCRprimers. The primers should contain restriction enzyme sites whichcorrespond to the restriction enzyme sites on the selected expressionvector. A variety of expression vectors may be employed. An example of asuitable vector is pBR322 (derived from E. coli; see Bolivar et al.,Gene, 2: 95 (1977)) which contains genes for ampicillin and tetracyclineresistance. The vector is digested with restriction enzyme anddephosphorylated. The PCR amplified sequences are then ligated into thevector. The vector will preferably include sequences which encode for anantibiotic resistance gene, a trp promoter, a polyhis leader (includingthe first six STII codons, polyhis sequence, and enterokinase cleavagesite), the PRO coding region, lambda transcriptional terminator, and anargU gene.

The ligation mixture is then used to transform a selected E. coli strainusing the methods described in Sambrook et al., supra. Transformants areidentified by their ability to grow on LB plates and antibioticresistant colonies are then selected. Plasmid DNA can be isolated andconfirmed by restriction analysis and DNA sequencing.

Selected clones can be grown overnight in liquid culture medium such asLB broth supplemented with antibiotics. The overnight culture maysubsequently be used to inoculate a larger scale culture. The cells arethen grown to a desired optical density, during which the expressionpromoter is turned on.

After culturing the cells for several more hours, the cells can beharvested by centrifugation. The cell pellet obtained by thecentrifugation can be solubilized using various agents known in the art,and the sotubilized PRO protein can then be purified using a metalchelating column under conditions that allow tight binding of theprotein.

PRO may be expressed in E. coli in a poly-His tagged form, using thefollowing procedure. The DNA encoding PRO is initially amplified usingselected PCR primers. The primers will contain restriction enzyme siteswhich correspond to the restriction enzyme sites on the selectedexpression vector, and other useful sequences providing for efficientand reliable translation initiation, rapid purification on a metalchelation column, and proteolytic removal with enterokinase. ThePCR-amplified, poly-His tagged sequences are then ligated into anexpression vector, which is used to transform an E. coli host based onstrain 52 (W3110 fuhA(tonA) lon galE rpoHts(htpRts) clpP(lacIq).Transformants are first grown in LB containing 50 mg/ml carbenicillin at30° C. with shaking until an O.D.600 of 3-5 is reached. Cultures arethen diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g(NH₄)₂SO₄, 0.71 g sodium citrate·2H2O, 1.07 g KCl, 5.36 g Difco yeastextract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mMMPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO₄) and grown forapproximately 20-30 hours at 30° C. with shaking. Samples are removed toverify expression by SDS-PAGE analysis, and the bulk culture iscentrifuged to pellet the cells. Cell pellets are frozen untilpurification and refolding.

E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) isresuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8buffer. Solid sodium sulfite and sodium tetrathionate is added to makefinal concentrations of 0.1M and 0.02 M, respectively, and the solutionis stirred overnight at 4° C. This step results in a denatured proteinwith all cysteine residues blocked by sulfitolization. The solution iscentrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. Thesupernatant is diluted with 3-5 volumes of metal chelate column buffer(6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micronfilters to clarify. The clarified extract is loaded onto a 5 ml QiagenNi-NTA metal chelate column equilibrated in the metal chelate columnbuffer. The column is washed with additional buffer containing 50 mMimidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted withbuffer containing 250 mM imidazole. Fractions containing the desiredprotein are pooled and stored at 4° C. Protein concentration isestimated by its absorbance at 280 nm using the calculated extinctioncoefficient based on its amino acid sequence.

The proteins are refolded by diluting the sample slowly into freshlyprepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCl,2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refoldingvolumes are chosen so that the final protein concentration is between 50to 100 micrograms/ml. The refolding solution is stirred gently at 4° C.for 12-36 hours. The refolding reaction is quenched by the addition ofTFA to a final concentration of 0.4% (pH of approximately 3). Beforefurther purification of the protein, the solution is filtered through a0.22 micron filter and acetonitrile is added to 2-10% finalconcentration. The refolded protein is chromatographed on a Poros R1/Hreversed phase column using a mobile buffer of 0.1% TFA with elutionwith a gradient of acetonitrile from 10 to 80%. Aliquots of fractionswith A280 absorbance are analyzed on SDS polyacrylamide gels andfractions containing homogeneous refolded protein are pooled. Generally,the properly refolded species of most proteins are eluted at the lowestconcentrations of acetonitrile since those species are the most compactwith their hydrophobic interiors shielded from interaction with thereversed phase resin. Aggregated species are usually eluted at higheracetonitrile concentrations. In addition to resolving misfolded forms ofproteins from the desired form, the reversed phase step also removesendotoxin from the samples.

Fractions containing the desired folded PRO polypeptide are pooled andthe acetonitrile removed using a gentle stream of nitrogen directed atthe solution. Proteins are formulated into 20 mM Hepes, pH 6.8 with 0.14M sodium chloride and 4% mannitol by dialysis or by gel filtration usingG25 Superfine (Pharmacia) resins equilibrated in the formulation bufferand sterile filtered.

Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 129 Expression of PRO in Mammalian Cells

This example illustrates preparation of a potentially glycosylated formof PRO by recombinant expression in mammalian cells.

The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), is employedas the expression vector. Optionally, the PRO DNA is ligated into pRK5with selected restriction enzymes to allow insertion of the PRO DNAusing ligation methods such as described in Sambrook et al., supra. Theresulting vector is called pRK5-PRO.

In one embodiment, the selected host cells may be 293 cells. Human 293cells (ATCC CCL 1573) are grown to confluence in tissue culture platesin medium such as DMEM supplemented with fetal calf serum andoptionally, nutrient components and/or antibiotics. About 10 μg pRK5-PRODNA is mixed with about 1 μg DNA encoding the VA RNA gene [Thimmappayaet al., Cell, 31: 543 (1982)] and dissolved in 500 μl of 1 mM Tris-HCl,0.1 mM EDTA, 0.227 M CaCl₂. To this mixture is added, dropwise, 500 μlof 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO₄, and a precipitateis allowed to form for 10 minutes at 25° C. The precipitate is suspendedand added to the 293 cells and allowed to settle for about four hours at37° C. The culture medium is aspirated off and 2 ml of 20% glycerol inPBS is added for 30 seconds. The 293 cells are then washed with serumfree medium, fresh medium is added and the cells are incubated for about5 days.

Approximately 24 hours after the transfections, the culture medium isremoved and replaced with culture medium (alone) or culture mediumcontaining 200 μCi/ml ³⁵S-cysteine and 200 μCi/ml ³⁵S-methionine. Aftera 12 hour incubation, the conditioned medium is collected, concentratedon a spin filter, and loaded onto a 15% SDS gel. The processed gel maybe dried and exposed to film for a selected period of time to reveal thepresence of PRO polypeptide. The cultures containing transfected cellsmay undergo further incubation (in serum free medium) and the medium istested in selected bioassays.

In an alternative technique, PRO may be introduced into 293 cellstransiently using the dextran sulfate method described by Somparyrac etal., Proc. Natl. Acad. Sci., 12: 7575 (1981). 293 cells are grown tomaximal density in a spinner flask and 700 μg pRK5-PRO DNA is added. Thecells are first concentrated from the spinner flask by centrifugationand washed with PBS. The DNA-dextran precipitate is incubated on thecell pellet for four hours. The cells are treated with 20% glycerol for90 seconds, washed with tissue culture medium, and re-introduced intothe spinner flask containing tissue culture medium, 5 μg/ml bovineinsulin and 0.1 μg/ml bovine transferrin. After about four days, theconditioned media is centrifuged and filtered to remove cells anddebris. The sample containing expressed PRO can then be concentrated andpurified by any selected method, such as dialysis and/or columnchromatography.

In another embodiment, PRO can be expressed in CHO cells. The pRK5-PROcan be transfected into CHO cells using known reagents such as CaPO₄ orDEAE-dextran. As described above, the cell cultures can be incubated,and the medium replaced with culture medium (alone) or medium containinga radiolabel such as ³⁵S-methionine. After determining the presence ofPRO polypeptide, the culture medium may be replaced with serum freemedium. Preferably, the cultures are incubated for about 6 days, andthen the conditioned medium is harvested. The medium containing theexpressed PRO can then be concentrated and purified by any selectedmethod.

Epitope-tagged PRO may also be expressed in host CHO cells. The PRO maybe subcloned out of the pRK5 vector. The subclone insert can undergo PCRto fuse in frame with a selected epitope tag such as a poly-his tag intoa Baculovirus expression vector. The poly-his tagged PRO insert can thenbe subcloned into a SV40 driven vector containing a selection markersuch as DHFR for selection of stable clones. Finally, the CHO cells canbe transfected (as described above) with the SV40 driven vector.Labeling may be performed, as described above, to verify expression. Theculture medium containing the expressed poly-His tagged PRO can then beconcentrated and purified by any selected method, such as byNi²⁺-chelate affinity chromatography.

PRO may also be expressed in CHO and/or COS cells by a transientexpression procedure or in CHO cells by another stable expressionprocedure.

Stable expression in CHO cells is performed using the followingprocedure. The proteins are expressed as an IgG construct(immunoadhesin), in which the coding sequences for the soluble forms(e.g. extracellular domains) of the respective proteins are fused to anIgG1 constant region sequence containing the hinge, CH2 and CH2 domainsand/or is a poly-His tagged form.

Following PCR amplification, the respective DNAs are subcloned in a CHOexpression vector using standard techniques as described in Ausubel etal., Current Protocols of Molecular Biology, Unit 3.16, John Wiley andSons (1997). CHO expression vectors are constructed to have compatiblerestriction sites 5′ and 3′ of the DNA of interest to allow theconvenient shuttling of cDNA's. The vector used expression in CHO cellsis as described in Lucas et al., Nucl. Acids Res. 24: 9 (1774-1779(1996), and uses the SV40 early promoter/enhancer to drive expression ofthe cDNA of interest and dihydrofolate reductase (DHFR). DHFR expressionpermits selection for stable maintenance of the plasmid followingtransfection.

Twelve micrograms of the desired plasmid DNA is introduced intoapproximately 10 million CHO cells using commercially availabletransfection reagents Superfect® (Quiagen), Dosper® or Fugene®(Boehringer Mannheim). The cells are grown as described in Lucas et al.,supra Approximately 3×10⁻⁷ cells are frozen in an ampule for furthergrowth and production as described below.

The ampules containing the plasmid DNA are thawed by placement intowater bath and mixed by vortexing. The contents are pipetted into acentrifuge tube containing 10 mLs of media and centrifuged at 1000 rpmfor 5 minutes. The supernatant is aspirated and the cells areresuspended in 10 mL of selective media (0.2 μm filtered PS20 with 5%0.2 μm diafiltered fetal bovine serum). The cells are then aliquotedinto a 100 mL spinner containing 90 mL of selective media. After 1-2days, the cells are transferred into a 250 mL spinner filled with 150 mLselective growth medium and incubated at 37° C. After another 2-3 days,250 mL, 500 mL and 2000 mL spinners are seeded with 3×10⁵ cells/mL. Thecell media is exchanged with fresh media by centrifugation andresuspension in production medium. Although any suitable CHO media maybe employed, a production medium described in U.S. Pat. No. 5,122,469,issued Jun. 16, 1992 may actually be used. A 3L production spinner isseeded at 1.2×10⁶ cells/mL. On day 0, the cell number pH ie determined.On day 1, the spinner is sampled and sparging with filtered air iscommenced. On day 2, the spinner is sampled, the temperature shifted to33° C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g.,35% polydimethylsiloxane emulsion, Dow Corning 365 Medical GradeEmulsion) taken. Throughout the production, the pH is adjusted asnecessary to keep it at around 7.2. After 10 days, or until theviability dropped below 70%, the cell culture is harvested bycentrifugation and filtering through a 0.22 μm filter. The filtrate waseither stored at 4° C. or immediately loaded onto columns forpurification.

For the poly-His tagged constructs, the proteins are purified using aNi-NTA column (Qiagen). Before purification, imidazole is added to theconditioned media to a concentration of 5 mM. The conditioned media ispumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4,buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5ml/min. at 4° C. After loading, the column is washed with additionalequilibration buffer and the protein eluted with equilibration buffercontaining 0.25 M imidazole. The highly purified protein is subsequentlydesalted into a storage buffer containing 10 mM Hepes, 0.14 M NaCl and4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column andstored at −80° C.

Immunoadhesin (Fc-containing) constructs are purified from theconditioned media as follows. The conditioned medium is pumped onto a 5ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Naphosphate buffer, pH 6.8. After loading, the column is washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein is immediately neutralized bycollecting 1 ml fractions into tubes containing 275 μL of 1 M Trisbuffer, pH 9. The highly purified protein is subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity is assessed by SDS polyacrylamide gels and by N-terminalamino acid sequencing by Edman degradation.

Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 130 Expression of PRO in Yeast

The following method describes recombinant expression of PRO in yeast.

First, yeast expression vectors are constructed for intracellularproduction or secretion of PRO from the ADH2/GAPDH promoter. DNAencoding PRO and the promoter is inserted into suitable restrictionenzyme sites in the selected plasmid to direct intracellular expressionof PRO. For secretion, DNA encoding PRO can be cloned into the selectedplasmid, together with DNA encoding the ADH2/GAPDH promoter, a nativePRO signal peptide or other mammalian signal peptide, or, for example, ayeast alpha-factor or invertase secretory signal/leader sequence, andlinker sequences (if needed) for expression of PRO.

Yeast cells, such as yeast strain AB110, can then be transformed withthe expression plasmids described above and cultured in selectedfermentation media. The transformed yeast supernatants can be analyzedby precipitation with 10% trichloroacetic acid and separation bySDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

Recombinant PRO can subsequently be isolated and purified by removingthe yeast cells from the fermentation medium by centrifugation and thenconcentrating the medium using selected cartridge filters. Theconcentrate containing PRO may further be purified using selected columnchromatography resins.

Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 131 Expression of PRO in Baculovirus-Infected Insect Cells

The following method describes recombinant expression of PRO inBaculovirus-infected insect cells.

The sequence coding for PRO is fused upstream of an epitope tagcontained within a baculovirus expression vector. Such epitope tagsinclude poly-his tags and immunoglobulin tags (like Fe regions of IgG).A variety of plasmids may be employed, including plasmids derived fromcommercially available plasmids such as pVL1393 (Novagen). Briefly, thesequence encoding PRO or the desired portion of the coding sequence ofPRO such as the sequence encoding the extracellular domain of atransmembrane protein or the sequence encoding the mature protein if theprotein is extracellular is amplified by PCR with primers complementaryto the 5′ and 3′ regions. The 5′ primer may incorporate flanking(selected) restriction enzyme sites. The product is then digested withthose selected restriction enzymes and subcloned into the expressionvector.

Recombinant baculovirus is generated by co-transfecting the aboveplasmid and BaculoGold™ virus DNA (Pharmingen) into Spodopterafrugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commerciallyavailable from GIBCO-BRL). After 4-5 days of incubation at 28° C., thereleased viruses are harvested and used for further amplifications.Viral infection and protein expression are performed as described byO'Reilley et al., Baculovirus expression vectors: A Laboratory Manual,Oxford: Oxford University Press (1994).

Expressed poly-his tagged PRO can then be purified, for example, byNi²⁺-chelate affinity chromatography as follows. Extracts are preparedfrom recombinant virus-infected Sf9 cells as described by Rupert et al.,Nature, 362: 175-179 (1993). Briefly, Sf9 cells are washed, resuspendedin sonication buffer (25 mL Hepes, pH 7.9; 12.5 mM MgCl₂; 0.1 mM EDTA;10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicated twice for 20 secondson ice. The sonicates are cleared by centrifugation, and the supernatantis diluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCl, 10%glycerol, pH 7.8) and filtered through a 0.45 μm filter. A Ni²⁺-NTAagarose column (commercially available from Qiagen) is prepared with abed volume of 5 mL, washed with 25 mL of water and equilibrated with 25mL of loading buffer. The filtered cell extract is loaded onto thecolumn at 0.5 mL per minute. The column is washed to baseline A₂₈₀ withloading buffer, at which point fraction collection is started. Next, thecolumn is washed with a secondary wash buffer (50 mM phosphate; 300 mMNaCl, 10% glycerol, pH 6.0), which elutes nonspecifically bound protein.After reaching A₂₈₀ baseline again, the column is developed with a 0 to500 mM Imidazole gradient in the secondary wash buffer. One mL fractionsare collected and analyzed by SDS-PAGE and silver staining or Westernblot with Ni²⁺-NTA-conjugated to alkaline phosphatase (Qiagen).Fractions containing the eluted His₁₀-tagged PRO are pooled and dialyzedagainst loading buffer.

Alternatively, purification of the IgG tagged (or Fc tagged) PRO can beperformed using known chromatography techniques, including for instance,Protein A or protein G column chromatography.

Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 132 Preparation of Antibodies that Bind PRO

This example illustrates preparation of monoclonal antibodies which canspecifically bind PRO.

Techniques for producing the monoclonal antibodies are known in the artand arc described, for instance, in Goding, supra. Immunogens that maybe employed include purified PRO, fusion proteins containing PRO, andcells expressing recombinant PRO on the cell surface. Selection of theimmunogen can be made by the skilled artisan without undueexperimentation.

Mice, such as Balb/c, are immunized with the PRO immunogen emulsified incomplete Freund's adjuvant and injected subcutaneously orintraperitoneally in an amount from 1-100 micrograms. Alternatively, theimmunogen is emulsified in MPL-TDM adjuvant (Ribi ImmunochemicalResearch, Hamilton, Mont.) and injected into the animal's hind footpads. The immunized mice are then boosted 10 to 12 days later withadditional immunogen emulsified in the selected adjuvant. Thereafter,for several weeks, the mice may also be boosted with additionalimmunization injections. Serum samples may be periodically obtained fromthe mice by retro-orbital bleeding for testing in ELISA assays to detectanti-PRO antibodies.

After a suitable antibody titer has been detected, the animals“positive” for antibodies can be injected with a final intravenousinjection of PRO. Three to four days later, the mice are sacrificed andthe spleen cells are harvested. The spleen cells are then fused (using35% polyethylene glycol) to a selected murine myeloma cell line such asP3X63AgU.1, available from ATCC, No. CRL 1597. The fusions generatehybridoma cells which can then be plated in 96 well tissue cultureplates containing HAT (hypoxanthine, aminopterin, and thymidine) mediumto inhibit proliferation of non-fused cells, myeloma hybrids, and spleencell hybrids.

The hybridoma cells will be screened in an ELISA for reactivity againstPRO. Determination of “positive” hybridoma cells secreting the desiredmonoclonal antibodies against PRO is within the skill in the art.

The positive hybridoma cells can be injected intraperitoneally intosyngeneic Balb/c mice to produce ascites containing the anti-PROmonoclonal antibodies. Alternatively, the hybridoma cells can be grownin tissue culture flasks or roller bottles. Purification of themonoclonal antibodies produced in the ascites can be accomplished usingammonium sulfate precipitation, followed by gel exclusionchromatography. Alternatively, affinity chromatography based uponbinding of antibody to protein A or protein G can he employed.

Example 133 Purification of PRO Polypeptides Using Specific Antibodies

Native or recombinant PRO polypeptides may be purified by a variety ofstandard techniques in the art of protein purification. For example,pro-PRO polypeptide, mature PRO polypeptide, or pre-PRO polypeptide ispurified by immunoaffinity chromatography using antibodies specific forthe PRO polypeptide of interest. In general, an immunoaffinity column isconstructed by covalently coupling the anti-PRO polypeptide antibody toan activated chromatographic resin.

Polyclonal immunoglobulins are prepared from immune sera either byprecipitation with ammonium sulfate or by purification on immobilizedProtein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise,monoclonal antibodies are prepared from mouse ascites fluid by ammoniumsulfate precipitation or chromatography on immobilized Protein A.Partially purified immunoglobulin is covalently attached to achromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKBBiotechnology). The antibody is coupled to the resin, the resin isblocked, and the derivative resin is washed according to themanufacturer's instructions.

Such an immunoaffinity column is utilized in the purification of PROpolypeptide by preparing a fraction from cells containing PROpolypeptide in a soluble form. This preparation is derived bysolubilization of the whole cell or of a subcellular fraction obtainedvia differential centrifugation by the addition of detergent or by othermethods well known in the art. Alternatively, soluble PRO polypeptidecontaining a signal sequence may be secreted in useful quantity into themedium in which the cells are grown.

A soluble PRO polypeptide-containing preparation is passed over theimmunoaffinity column, and the column is washed under conditions thatallow the preferential absorbance of PRO polypeptide (e.g., high ionicstrength buffers in the presence of detergent). Then, the column iseluted under conditions that disrupt antibody/PRO polypeptide binding(e.g., a low pH buffer such as approximately pH 2-3, or a highconcentration of a chaotrope such as urea or thiocyanate ion), and PROpolypeptide is collected.

Example 134 Drug Screening

This invention is particularly useful for screening compounds by usingPRO polypeptides or binding fragment thereof in any of a variety of drugscreening techniques. The PRO polypeptide or fragment employed in such atest may either be free in solution, affixed to a solid support, borneon a cell surface, or located intracellularly. One method of drugscreening utilizes eukaryotic or prokaryotic host cells which are stablytransformed with recombinant nucleic acids expressing the PROpolypeptide or fragment. Drugs are screened against such transformedcells in competitive binding assays. Such cells, either in viable orfixed form, can be used for standard binding assays. One may measure,for example, the formation of complexes between PRO polypeptide or afragment and the agent being tested. Alternatively, one can examine thediminution in complex formation between the PRO polypeptide and itstarget cell or target receptors caused by the agent being tested.

Thus, the present invention provides methods of screening for drugs orany other agents which can affect a PRO polypeptide-associated diseaseor disorder. These methods comprise contacting such an agent with an PROpolypeptide or fragment thereof and assaying (I) for the presence of acomplex between the agent and the PRO polypeptide or fragment, or (ii)for die presence of a complex between the PRO polypeptide or fragmentand the cell, by methods well known in the art. In such competitivebinding assays, the PRO polypeptide or fragment is typically labeled.After suitable incubation, free PRO polypeptide or fragment is separatedfrom that present in bound form, and the amount of free or uncomplexedlabel is a measure of the ability of the particular agent to bind to PROpolypeptide or to interfere with the PRO polypeptide/cell complex.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity to a polypeptide and isdescribed in detail in WO 84/03564, published on Sep. 13, 1984. Brieflystated, large numbers of different small peptide test compounds aresynthesized on a solid substrate, such as plastic pins or some othersurface. As applied to a PRO polypeptide, the peptide test compounds arereacted with PRO polypeptide and washed. Bound PRO polypeptide isdetected by methods well known in the art. Purified PRO polypeptide canalso be coated directly onto plates for use in the aforementioned drugscreening techniques. In addition, non-neutralizing antibodies can beused to capture the peptide and immobilize it on the solid support.

This invention also contemplates the use of competitive drug screeningassays in which neutralizing antibodies capable of binding PROpolypeptide specifically compete with a test compound for binding to PROpolypeptide or fragments thereof. In this manner, the antibodies can beused to detect the presence of any peptide which shares one or moreantigenic determinants with PRO polypeptide.

Example 135 Rational Drug Design

The goal of rational drug design is to produce structural analogs ofbiologically active polypeptide of interest (i.e., a PRO polypeptide) orof small molecules with which they interact. e.g., agonists,antagonists, or inhibitors. Any of these examples can be used to fashiondrugs which are more active or stable forms of the PRO polypeptide orwhich enhance or interfere with the function of the PRO polypeptide invivo (c.f., Hodgson, Bio/Technology, 9: 19-21 (1991)).

In one approach, the three-dimensional structure of the PRO polypeptide,or of an PRO polypeptide-inhibitor complex, is determined by x-raycrystallography, by computer modeling or, most typically, by acombination of the two approaches. Both the shape and charges of the PROpolypeptide must be ascertained to elucidate the structure and todetermine active site(s) of the molecule. Less often, useful informationregarding the structure of the PRO polypeptide may be gained by modelingbased on the structure of homologous proteins. In both cases, relevantstructural information is used to design analogous PRO polypeptide-likemolecules or to identify efficient inhibitors. Useful examples ofrational drug design may include molecules which have improved activityor stability as shown by Braxton and Wells, Biochemistry, 31: 7796-7801(1992) or which act as inhibitors, agonists, or antagonists of nativepeptides as shown by Athauda et al., J. Biochem., 113: 742-746 (1993).

It is also possible to isolate a target-specific antibody, selected byfunctional assay, as described above, and then to solve its crystalstructure. This approach, in principle, yields a pharmacore upon whichsubsequent drug design can be based. It is possible to bypass proteincrystallography altogether by generating anti-idiotypic antibodies(anti-ids) to a functional, pharmacologically active antibody. As amirror image of a mirror image, the binding site of the anti-ids wouldbe expected to be an analog of the original receptor. The anti-id couldthen be used to identify and isolate peptides from banks of chemicallyor biologically produced peptides. The isolated peptides would then actas the pharmacore.

By virtue of the present invention, sufficient amounts of the PROpolypeptide may be made available to perform such analytical studies asX-ray crystallography. In addition, knowledge of the PRO polypeptideamino acid sequence provided herein will provide guidance to thoseemploying computer modeling techniques in place of or in addition tox-ray crystallography.

Example 136 Stimulation of Endothelial Cell Proliferation (Assay 8)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to stimulate adrenal corticalcapillary endothelial cell (ACE) growth. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of conditions or disorders where angiogenesiswould be beneficial including, for example, wound healing, and the like(as would agonists of these PRO polypeptides). Antagonists of the PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of cancerous tumors.

Bovine adrenal cortical capillary endothelial (ACE) cells (from primaryculture, maximum of 12-14 passages) were plated in 96-well plates at 500cells/well per 100 microliter. Assay media included low glucose DMEM,10% calf serum, 2 mM glutamine, and 1×penicillin/streptomycin/fungizone. Control wells included the following:(1) no ACE cells added; (2) ACE cells alone; (3) ACE cells plus VEGF (5ng/ml); and (4) ACE cells plus FGF (5ng/ml). The control or test sample,(in 100 microliter volumes), was then added to the wells (at dilutionsof 1%, 0.1% and 0.01%, respectively). The cell cultures were incubatedfor 6-7 days at 37° C./5% CO₂. After the incubation, the media in thewells was aspirated, and the cells were washed 1× with PBS. An acidphosphatase reaction mixture (100 microliter; 0.1M sodium acetate, pH5.5, 0.1% Triton X-100, 10 mM p-nitrophenyl phosphate) was then added toeach well. After a 2 hour incubation at 37° C., the reaction was stoppedby addition of 10 microliters 1N NaOH. Optical density (OD) was measuredon a microplate reader at 405 nm.

The activity of a PRO polypeptide was calculated as the fold increase inproliferation (as determined by the acid phosphatase activity, OD 405nm) relative to (1) cell only background, and (2) relative to maximumstimulation by VEGF. VEGF (at 3-10 ng/ml) and FGF (at 1-5 ng/ml) wereemployed as an activity reference for maximum stimulation. Results ofthe assay were considered “positive” if the observed stimulation was≧50% increase over background. VEGF (5 ng/ml) control at 1% dilutiongave 1.24 fold stimulation; FGF (5 ng/ml) control at 1% dilution gave1.46 fold stimulation.

The following PRO polypeptides tested positive in this assay: PRO1244,PRO1286 and PRO1303.

Example 137 Inhibitory Activity in Mixed Lvmphocyte Reaction (MLR) Assay(Assay 67)

This example shows that one or more of the polypeptides of the inventionare active as inhibitors of the proliferation of stimulatedT-lymphocytes. Compounds which inhibit proliferation of lymphocytes areuseful therapeutically where suppression of an immune response isbeneficial.

The basic protocol for this assay is described in Current Protocols inImmunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by Inhn Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclearcells (PBMC) are isolated from mammalian individuals, for example ahuman volunteer, by leukopheresis (one donor will supply stimulatorPBMCs, the other donor will supply responder PBMCs). If desired, thecells are frozen in fetal bovine serum and DMSO after isolation. Frozencells may be thawed overnight in assay media (37° C., 5% CO₂) and thenwashed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetalbovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

-   -   100:1 of test sample diluted to 1% or to 0.1%,    -   50:1 of irradiated stimulator cells, and    -   50:1 of responder PBMC cells.        100 microliters of cell culture media or 100 microliter of        CD4-IgG is used as the control. The wells are then incubated at        37° C., 5% CO₂ for 4 days. On day 5, each well is pulsed with        tritiated thymidine (1.0 mC/well; Amersham). After 6 hours the        cells are washed 3 times and then the uptake of the label is        evaluated.

In another variant of this assay, PBMCs are isolated from the spleens ofBalb/c mice and C57B6 mice. The cells are teased from freshly harvestedspleens in assay media (RPMI: 10% fetal bovine serum, 1%penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential aminoacids, 1% pyruvate) and the PBMCs are isolated by overlaying these cellsover Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20minutes, collecting and washing the mononuclear cell layer in assaymedia and resuspending the cells to 1×10⁷ cells/ml of assay media. Theassay is then conducted as described above.

Any decreases below control is considered to be a positive result for aninhibitory compound, with decreases of less than or equal to 80% beingpreferred. However, any value less than control indicates an inhibitoryeffect for the test protein.

The following polypeptide tested positive in this assay: PRO1250,PRO1418 and PRO1410.

Example 138 Stimulation of Heart Neonatal Hypertrophy (Assay 1)

This assay is designed to measure the ability of PRO polypeptides tostimulate hypertrophy of neonatal heart. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of various cardiac insufficiency disorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats wereobtained. Cells (180 μl at 7.5×10⁴/ml, serum <0.1%, freshly isolated)are added on day 1 to 96-well plates previously coated with DMEM/F12+4%FCS. Test samples containing the test PRO polypeptide are added directlyto wells on day 2 in 20 μL volumes. Cells are stained with crystalviolet after an additional two days and scored visually by the next day.Incubator conditions require 5% CO₂.

Activity reference: phenylephrine at 1-100 μM, PGF-2 alpha at 0.1-1.0μM, endothelin-1 at 1-10 nM, CT1 (LIF) at 1-10 nM. No PBS is included,since calcium concentration is critical for assay response. Assay mediaincluded: DMEM/F12 (with 2.44 gm bicarbonate), 10 μg/ml transferrin, 1μg/ml insulin, 1 μg/ml aprotinin, 2 mmol/L glutamine, 100 U/mlpenicillin G, 100 μg/ml streptomycin. Protein buffer containing mannitol(4%) gave a positive signal (score 3.5) at 1/10 (0.4%) and 1/100(0.04%), but not at 1/1000 (0.004%). Therefore, the test sample buffercontaining mannitol is not run. A secondary assay consists of measuringthe ANP levels (ng/ml) by ELISA in conditioned media from the cells. Anincrease in the ANP message can be measured by PCR from cells after afew hours.

Results are assessed by visually observing cell size: a score=3.5 orgreater is considered positive for conditioned media; a score of 3.0 orgreater is considered positive for purified protein.

The following purified PRO polypeptide was observed to stimulateneonatal heart hypertrophy in this assay: PRO1246.

Example 139 Inhibition of Vascular Endothelial Growth Factor (VEGF)Stimulated Proliferation of Endothelial Cell Growth (Assay 9)

The ability of various PRO polypeptides to inhibit VEGF stimulatedproliferation of endothelial cells was tested. Polypeptides testingpositive in this assay are useful for inhibiting endothelial cell growthin mammals where such an effect would be beneficial, e.g., forinhibiting tumor growth.

Specifically, bovine adrenal cortical capillary endothelial cells (ACE)(from primary culture, maximum of 12-14 passages) were plated in 96-wellplates at 500 cells/well per 100 microliter. Assay media included lowglucose DMEM, 10% calf serum, 2 mM glutamine, and 1×penicillin/streptomycin/fungizone. Control wells included the following:(1) no ACE cells added; (2) ACE cells alone; (3) ACE cells plus 5 ng/mlFGF; (4) ACE cells plus 3 ng/ml VEGF; (5) ACE cells plus 3 ng/ml VEGFplus 1 ng/ml TGF-beta; and (6) ACE cells plus 3 ng/ml VEGF plus 5 ng/mlLIF. The test samples, poly-his tagged PRO polypeptides (in 100microliter volumes), were then added to the wells (at dilutions of 1%,0.1% and 0.01%, respectively). The cell cultures were incubated for 6-7days at 37° C./5% CO₂. After the incubation, the media in the wells wasaspirated, and the cells were washed 1× with PBS. An acid phosphatasereaction mixture (100 microliter; 0.1M sodium acetate, pH 5.5, 0.1%Triton X-100, 10 mM p-nitrophenyl phosphate) was then added to eachwell. After a 2 hour incubation at 37° C., the reaction was stopped byaddition of 10 microliters 1N NaOH. Optical density (OD) was measured ona microplate reader at 405 nm.

The activity of PRO polypeptides was calculated as the percentinhibition of VEGF (3 ng/ml) stimulated proliferation (as determined bymeasuring acid phosphatase activity at OD 405 nm) relative to the cellswithout stimulation. TGF-beta was employed as an activity reference at 1ng/ml, since TGF-beta blocks 70-90% of VEGF-stimulated ACE cellproliferation. The results are indicative of the utility of the PROpolypeptides in cancer therapy and specifically in inhibiting tumorangiogenesis. Numerical values (relative inhibition) are determined bycalculating the percent inhibition of VEGF stimulated proliferation bythe PRO polypeptides relative to cells without stimulation and thendividing that percentage into the percent inhibition obtained by TGF-βat1 ng/ml which is known to block 70-90% of VEGF stimulated cellproliferation. The results are considered positive if the PROpolypeptide exhibits 30% or greater inhibition of VEGF stimulation ofendothelial cell growth (relative inhibition 30% or greater).

The following polypeptide tested positive in this assay: PRO1246.

Example 140 Human Venous Endothelial Cell Calcium Flux Assay (Assay 68)

This assay is designed to determine whether PRO polypeptides show theability to stimulate calcium flux in human umbilical vein endothelialcells (HUVEC, Cell Systems). Calcium influx is a well documentedresponse upon binding of certain ligands to their receptors. A testcompound that results in a positive response in the present calciuminflux assay can be said to bind to a specific receptor and activate abiological signaling pathway in human endothelial cells. This willultimately lead, for example, to cell division, inhibition of cellproliferation, endothelial tube formation, cell migration, apoptosis,etc.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) ingrowth media (50:50 without glycine, 1% glutamine, 10 μM Hepes, 10% FBS,10 ng/ml bFGF), were plated on 96-well microtiter ViewPlates-96 (PackardInstrument Company Part #6005182) microtiter plates at a cell density of2×10⁴ cells/well. The day after plating, the cells were washed threetimes with buffer (HBSS plus 10 mM Hepes), leaving 100 μl/well. Then 100μl/well of 8 μM Fluo-3 (2×) was added. The cells were incubated for 1.5hours at 37° C./5% CO₂. After incubation, the cells were then washed 3×with buffer (described above) leaving 100 μl/well. Test samples of thePRO polypeptides were prepared on different 96-well plates at 5×concentration in buffer. The positive control corresponded to 50 μMionomycin (5×); the negative control corresponded to Protein 32. Cellplate and sample plates were run on a FLIPR (Molecular Devices) machine.The FLIPR machine added 25 μl of test sample to the cells, and readingswere taken every second for one minute, then every 3 seconds for thenext three minutes.

The fluorescence change from baseline to the maximum rise of the curve(Δ change) was calculated, and replicates averaged. The rate offluorescence increase was monitored, and only those samples which had aΔ change greater than 1000 and a rise within 60 seconds, were consideredpositive.

The following PRO polypeptides tested positive in this assay: PRO1246and PRO1561.

Example 141 Skin Vascular Permeability Assay (Assay 64)

This assay shows that certain polypeptides of the invention stimulate animmune response and induce inflammation by inducing mononuclear cell,eosinophil and PMN infiltration at the site of injection of the animal.Compounds which stimulate an immune response arc useful therapeuticallywhere stimulation of an immune response is beneficial. This skinvascular permeability assay is conducted as follows. Hairless guineapigs weighing 350 grams or more are anesthetized with ketamine (75-80mg/Kg) and 5 mg/Kg xylazine intramuscularly (IM). A sample of purifiedpolypeptide of the invention or a conditioned media test sample isinjected intradermally onto the backs of the test animals with 100 μlper injection site. It is possible to have about 10-30, preferably about16-24, injection sites per animal. One μl of Evans blue dye (1% inphysiologic buffered saline) is injected intracardially. Blemishes atthe injection sites are then measured (mm diameter) at 1 hr and 6 hrpost injection. Animals were sacrificed at 6 hrs after injection. Eachskin injection site is biopsied and fixed in formalin. The skins arethen prepared for histopathologic evaluation. Each site is evaluated forinflammatory cell infiltration into the skin. Sites with visibleinflammatory cell inflammation are scored as positive. Inflammatorycells may be neutrophilic, eosinophilic, monocytic or lymphocytic. Atleast a minimal perivascular infiltrate at the injection site is scoredas positive, no infiltrate at the site of injection is scored asnegative.

The following polypeptide tested positive in this assay: PRO1283,PRO1325 and PRO1343.

Example 142 Induction of c-fos in Endothelial Cells (Assay 34)

This assay is designed to determine whether PRO polypeptides show theability to induce c-fos in endothelial cells. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of conditions or disorders where angiogenesiswould be beneficial including, for example, wound healing, and the like(as would agonists of these PRO polypeptides). Antagonists of the PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of cancerous tumors.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) ingrowth media (50% Ham's F12 w/o GHT: low glucose, and 50% DMEM withoutglycine: with NaHCO3, 1% glutamine, 10 mM HEPES, 10% FBS, 10 ng/ml bFGF)were plated on 96-well microtiter plates at a cell density of1×10⁴cells/well. The day after plating, the cells were starved byremoving the growth media and treating the cells with 100 μl/well testsamples and controls (positive control=growth media; negativecontrol=Protein 32 buffer=10 mM HEPES, 140 mM NaCl, 4% (w/v) mannitol,pH 6.8). The cells were incubated for 30 minutes at 37”° C., in 5% CO₂.The samples were removed, and the first part of the bDNA kit protocol(Chiron Diagnostics, cat. #6005-037) was followed, where eachcapitalized reagent/buffer listed below was available from the kit.

Briefly, the amounts of the TM Lysis Buffer and Probes needed for thetests were calculated based on information provided by the manufacturer.The appropriate amounts of thawed Probes were added to the TM LysisBuffer. The Capture Hybridization Buffer was warmed to room temperature.The bDNA strips were set up in the metal strip holders, and 100 μl ofCapture Hybridization Buffer was added to each b-DNA well needed,followed by incubation for at least 30 minutes. The test plates with thecells were removed from the incubator, and the media was gently removedusing the vacuum manifold. 100 μl of Lysis Hybridization Buffer withProbes were quickly pipetted into each well of the microtiter plates.The plates were then incubated at 55° C. for 15 minutes. Upon removalfrom the incubator, the plates were placed on the vortex mixer with themicrotiter adapter head and vortexed on the #2 setting for one minute.80 μl of the lysate was removed and added to the bDNA wells containingthe Capture Hybridization Buffer, and pipetted up and down to mix. Theplates were incubated at 53° C. for at least 16 hours.

On the next day, the second part of the bDNA kit protocol was followed.Specifically, the plates were removed from the incubator and placed onthe bench to cool for 10 minutes. The volumes of additions needed werecalculated based upon information provided by the manufacturer. AnAmplifier Working Solution was prepared by making a 1:100 dilution ofthe Amplifier Concentrate (20 fm/μl) in AL Hybridization Buffer. Thehybridization mixture was removed from the plates and washed twice withWash A. 50 μl of Amplifier Working Solution was added to each well andthe wells were incubated at 53° C. for 30 minutes. The plates were thenremoved from the incubator and allowed to cool for 10 minutes. The LabelProbe Working Solution was prepared by making a 1:100 dilution of LabelConcentrate (40 pmoles/μl) in AL Hybridization Buffer. After the10-minute cool-down period, the amplifier hybridization mixture wasremoved and the plates were washed twice with Wash A. 50 μl of LabelProbe Working Solution was added to each well and the wells wereincubated at 53° C. for 15 minutes. After cooling for 10 minutes, theSubstrate was warmed to room temperature. Upon addition of 3 μl ofSubstrate Enhancer to each ml of Substrate needed for the assay, theplates were allowed to cool for 10 minutes, the label hybridizationmixture was removed, and the plates were washed twice with Wash A andthree times with Wash D. 50 μl of the Substrate Solution with Enhancerwas added to each well. The plates were incubated for 30 minutes at 37°C. and RLU was read in an appropriate luminometer.

The replicates were averaged and the coefficient of variation wasdetermined. The measure of activity of the fold increase over thenegative control (Protein 32/HEPES buffer described above) value wasindicated by chemiluminescence units (RLU). The results are consideredpositive if the PRO polypeptide exhibits at least a two-fold value overthe negative buffer control. Negative control=1.00 RLU at 1.00%dilution. Positive control=8.39 RLU at 1.00% dilution.

The following PRO polypeptides tested positive in this assay: PRO1274,PRO1294, PRO1304 and PRO1130.

Example 143 Gene Amplification

This example shows that the PRO1295-, PRO1293-, PRO1265-, PRO1303-,PRO1269-, PRO1410-, PRO1317-, PRO1780-, PRO1555-, PRO1755-, PRO1558-,PRO1759- and PRO1788-encoding genes are amplified in the genome ofcertain human lung, colon and/or breast cancers and/or cell lines.Amplification is associated with overexpression of the gene product,indicating that the polypeptides are useful targets for therapeuticintervention in certain cancers such as colon, lung, breast and othercancers. Therapeutic agents may take the form of antagonists of PRO1295,PRO1293, PRO1265, PRO1303, PRO1269, PRO1410, PRO1317, PRO1780, PRO1555,PRO1755, PRO1558, PRO1759 and PRO1788 polypeptides, for example,murine-human chimeric, humanized or human antibodies against a PRO1295,PRO1293, PRO1265, PRO1303, PRO1269, PRO1410, PRO1317, PRO1780, PRO1555,PRO1755, PRO1558, PRO1759 or PRO1788 polypeptide.

The starting material for the screen was genomic DNA isolated from avariety of cancers. The DNA is quantitated precisely, e.g.,fluorometrically. As a negative control, DNA was isolated from the cellsof ten normal healthy individuals which was pooled and used as assaycontrols for the gene copy in healthy individuals (not shown). The 5′nuclease assay (for example, TaqMan™) and real-time quantitative PCR(for example, ABI Prizm 7700 Sequence Detection System™ (Perkin Elmer,Applied Biosystems Division, Foster City, Calif.)), were used to findgenes potentially amplified in certain cancers. The results were used todetermine whether the DNA encoding PRO1295, PRO1293, PRO1265, PRO1303,PRO1269, PRO1410, PRO1317, PRO1780, PRO1555, PRO1755, PRO1558, PRO1759and PRO1788 is over-represented in any of the primary lung or coloncancers or cancer cell lines or breast cancer cell lines that werescreened. The primary lung cancers were obtained from individuals withtumors of the type and stage as indicated in Table 7. An explanation ofthe abbreviations used for the designation of the primary tumors listedin Table 7 and the primary tumors and cell lines referred to throughoutthis example has been given hereinbefore.

The results of the TaqMan™ are reported in delta (Δ) Ct units. One unitcorresponds to 1 PCR cycle or approximately a 2-fold amplificationrelative to normal, two units corresponds to 4-fold, 3 units to 8-foldamplification and so on. Quantitation was obtained using primers and aTaqMan™ fluorescent probe derived from the PRO1295-, PRO1293-, PRO1265-,PRO1303-, PRO1269-, PRO1410-, PRO1317-, PRO1780-, PRO1555-, PRO1755-,PRO1558-, PRO1759- and PRO1788encoding gene. Regions of PRO1295,PRO1293, PRO1265, PRO1303, PRO1269, PRO1410, PRO1317, PRO1780, PRO1555,PRO1755, PRO1558, PRO1759 and PRO1788 which are most likely to containunique nucleic acid sequences and which are least likely to have splicedout introns are preferred for the primer and probe derivation, e.g.,3′-untranslated regions. The sequences for the primers and probes(forward, reverse and probe) used for the PRO1295, PRO1293, PRO1265,PRO1303, PRO1269, PRO1410, PRO1317, PRO1780, PRO1555, PRO1755, PRO1558,PRO1759 and PRO1788 gene amplification analysis were as follows:

PRO1295 (DNA59218-1559) forward: 5′-AGGACTTGCCCTCAGGAA-3′ (SEQ IDNO:432) reverse: 5′-CGCAGGACAGTTGTGAAAATA-3′ (SEQ ID NO:433) probe:5′-ATGACGCTCGTCCAAGGCCAC-3′ (SEQ ID NO:434) PRO1293 (DNA6O618-1557)forward: 5′-CCCACCTGTACCACCATGT-3′ (SEQ ID NO:435) probe:5′-ACTCCAGGCACCATCTGTTCTCCC-3′ (SEQ ID NO:436) reverse:5′-AAGGGCTGGCATTCAAGTU-3′ (SEQ ID NO:437) PRO1265 (DNA60764-1533)forward: 5′-TGACCTGGCAAAGGAAGAA-3′ (SEQ ID NO:438) probe:5′-CAGCCACCCTCCAGTCCAAGG-3′ (SEQ ID NO:439) reverse: 5′-GGGTCGTGTTTTGGAGAGA-3′ (SEQ ID NO:440) PRO1303 (DNA65409-1566) forward:5′-CTGGCCCTCAGAGCACCAAT-3′ (SEQ ID NO:441) probe:5′-TCCTCCATCACTTCCCCTAGCTCCA-3′ (SEQ ID NO:442) reverse:5′-CTGGCAGGAGTTAAAGTTCCAAGA-3′ (SEQ ID NO:443) PRO1269 (DNA66520-1536)forward: 5′ -AAAGGACACCGGGATGTG-3′ (SEQ ID NO:444) probe: 5′-AGCGTACACTCTCTCCAGGCAACCAG-3′ (SEQ ID NO:445) reverse: 5′-CAATTCTGGATGAGGTGGTAGA-3′ (SEQ ID NO:446) PRO1410 (DNA68874-1622)forward: 5′-CAGGACTGAGCGCTTGTTTA-3′ (SEQ ID NO:447) probe:5′-CAAAGCGCCAAGTACCGGACC-3′ (SEQ ID NO:448) reverse:5′-CCAGACCTCAGCCAGGAA-3′ (SEQ ID NO:449) PRO1317 (DNA71166-1685)forward: 5′-CCCTAGCTGACCCCTTCA-3′ (SEQ ID NO:450) reverse:5′-TCTGACAAGCAGTTTTCTGAATC-3′ (SEQ ID NO:451) probe:5′-CTCTCCCCCTCCCTTTTCCTTTGTTT-3′ (SEQ ID NO:452) PRO1780 (DNA71169-1709)forward: 5′ -CTCTGGTGCCCACAGTGA-3′ (SEQ ID NO:453) probe:5′-CCATGCCTGCTCAGCCAAGAA-3′ (SEQ ID NO:454) reverse:5′-CAGGAAATCTGGAAACCTACAGT-3′ (SEQ ID NO:455) PRO1555 (DNA73744-1665)forward: 5′-CCTTGAAAAGGACCCAGTTT-3′ (SEQ ID NO:456) probe:5′-ATGAGTCGCACCTGCTGTTCCC-3′ (SEQ ID NO:457) reverse:5′-TAGCAGCTGCCCTTGGTA-3′ (SEQ ID NO:458) forward:5′-AACAGCAGGTGCGACTCATCTA-3′ (SEQ ID NO:459) probe:5′-TGCTAGGCGACGACACCCAGACC-3′ (SEQ ID NO:460) reverse:5′-TGGACACGTGGCAGTGGA-3′ (SEQ ID NO:461) PRO1755 (DNA76396-1698)forward: 5′-TCATGGTCTCGTCCCATTC-3′ (SEQ ID NO:462) probe:5′-CACCATTTGTTTCTCTGTCTCCCCATC-3′ (SEQ ID NO:463) reverse:5′-CCGGCATCCTTGGAGTAG-3′ (SEQ ID NO:464) PRO1788 (DNA77652-2505)forward: 5′-TCCCCATTAGCACAGGAGTA-3′ (SEQ ID NO:465) probe: 5′-AGGCTCTTGCCTGTCCTGCTGCT-3′ (SEQ ID NO:466) reverse:5′-GCCCAGAGTCCCACTTGT-3′ (SEQ ID NO:467) PRO1558 (DNA71282-1668)forward: 5′-ACTGCTCCGCCTACTACGA-3′ (SEQ ID NO:468) probe:5′-AGGCATCCTCGCCGTCCTCA-3′ (SEQ ID NO:469) reverse:5′-AAGGCCAAGGTGAGTCCAT-3′ (SEQ ID NO:470) forward:5′-CGAGTGTGTGCGAAACCTAA-3′ (SEQ ID NO:471) probe:5′-TCAGGGTCTACATCAGCCTCCTGC-3′ (SEQ ID NO:472) reverse:5′-AAGGCCAAGGTGAGTCCAT-3′ (SEQ ID NO:473) PRO1759 (DNA76531-1701)forward: 5′-CCTACTGAGGAGCCCTATGC-3′ (SEQ ID NO:474) probe:5′-CCTGAGCTGTAACCCCACTCCAGG-3′ (SEQ ID NO:231) reverse:5′-AGAGTCTGTCCCAGCTATCTTGT-3′ (SEQ ID NO:232)

The 5′ nuclease assay reaction is a fluorescent PCR-based techniquewhich makes use of the 5′ exonuclease activity of Taq DNA polymeraseenzyme to monitor amplification in real time. Two oligonucleotideprimers are used to generate an amplicon typical of a PCR reaction. Athird oligonucleotide, or probe, is designed to detect nucleotidesequence located between the two PCR primers. The probe isnon-extendible by Taq DNA polymerase enzyme, and is labeled with areporter fluorescent dye and a quencher fluorescent dye. Anylaser-induced emission from the reporter dye is quenched by thequenching dye when the two dyes are located close together as they areon the probe. During the amplification reaction, the Taq DNA polymeraseenzyme cleaves the probe in a template-dependent manner. The resultantprobe fragments disassociate in solution, and signal from the releasedreporter dye is free from the quenching effect of the secondfluorophore. One molecule of reporter dye is liberated for each newmolecule synthesized, and detection of the unquenched reporter dyeprovides the basis for quantitative interpretation of the data.

The 5′ nuclease procedure is run on a real-time quantitative PCR devicesuch as the ABI Prism 7700TM Sequence Detection. The system consists ofa thermocycler, laser, charge-coupled device (CCD) camera and computer.The system amplifies samples in a 96-well format on a thermocycler.During amplification, laser-induced fluorescent signal is collected inreal-time through fiber optics cables for all 96 wells, and detected atthe CCD. The system includes software for running the instrument and foranalyzing the data.

5′ Nuclease assay data arc initially expressed as Ct, or the thresholdcycle. This is defined as the cycle at which the reporter signalaccumulates above the background level of fluorescence. The ΔCt valuesare used as quantitative measurement of the relative number of startingcopies of a particular target sequence in a nucleic acid sample whencomparing cancer DNA results to normal human DNA results.

Table 7 describes the stage, T stage and N stage of various primarytumors which were used to screen the PRO1295, PRO1293, PRO1265, PRO1303,PRO1269, PRO1410, PRO1317, PRO1780, PRO1555, PRO1755, PRO1558, PRO1759and PRO1788 compounds of the invention.

TABLE 7 Primary Lung and Colon Tumor Profiles Primary Tumor Stage OtherStage Dukes Stage T Stage N Stage Human lung tumor AdenoCa (SRCC724)[LT1] IIA T1 N1 Human lung tumor SqCCa (SRCC725) [LT1a] IIB T3 N0 Humanlung tumor AdenoCa (SRCC726) [LT2] IB T2 N0 Human lung tumor AdenoCa(SRCC727) [LT3] IIIA T1 N2 Human lung tumor AdenoCa (SRCC728) [LT4] IBT2 N0 Human lung tumor SqCCa (SRCC729) [LT6] IB T2 N0 Human lung tumorAden/SqCCa (SRCC730) [LT7] IA T1 N0 Human lung tumor AdenoCa (SRCC731)[LT9] IB T2 N0 Human lung tumor SqCCa (SRCC732) [LT10] IIB T2 N1 Humanlung tumor SqCCa (SRCC733) [LT11] IIA T1 N1 Human lung tumor AdenoCa(SRCC734) [LT12] IV T2 N0 Human lung tumor AdenoSqCCa (SRCC735) [LT13]IB T2 N0 Human lung tumor SqCCa (SRCC736) [LT15] IB T2 N0 Human lungtumor SqCCa (SRCC737) [LT16] IB T2 N0 Human lung tumor SqCCa (SRCC738)[LT17] IIB T2 N1 Human lung tumor SqCCa (SRCC739) [LT18] IB T2 N0 Humanlung tumor SqCCa (SRCC740) [LT19] IB T2 N0 Human lung tumor LCCa(SRCC741) [LT21] IIB T3 N1 Human lung AdenoCa (SRCC811) [LT22] 1A T1 N0Human colon AdenoCa (SRCC742) [CT2] M1 D pT4 N0 Human colon AdenoCa(SRCC743) [CT3] B pT3 N0 Human colon AdenoCa (SRCC744) [CT8] B T3 N0Human colon AdenoCa (SRCC745) [CT10] A pT2 N0 Human colon AdenoCa(SRCC746) [CT12] MO, R1 B T3 N0 Human colon AdenoCa (SRCC747) [CT14]pMO, RO B pT3 pN0 Human colon AdenoCa (SRCC748) [CT15] M1, R2 D T4 N2Human colon AdenoCa (SRCC749) [CT16] pMO B pT3 pN0 Human colon AdenoCa(SRCC750) [CT17] C1 pT3 pN1 Human colon AdenoCa (SRCC751) [CT1] MO, R1 BpT3 N0 Human colon AdenoCa (SRCC752) [CT4] B pT3 M0 Human colon AdenoCa(SRCC753) [CT5] G2 C1 pT3 pN0 Human colon AdenoCa (SRCC754) [CT6] pMO,RO B pT3 pN0 Human colon AdenoCa (SRCC755) [CT7] G1 A pT2 pN0 Humancolon AdenoCa (SRCC756) [CT9] G3 D pT4 pN2 Human colon AdenoCa (SRCC757)[CT11] B T3 N0 Human colon AdenoCa (SRCC758) [CT18] MO, RO B pT3 pN0DNA Preparation:

DNA was prepared from cultured cell lines, primary tumors, and normalhuman blood. The isolation was performed using purification kit, bufferset and protease and all from Qiagen, according to the manufacturer'sinstructions and the description below.

Cell Culture Lysis:

Cells were washed and trypsinized at a concentration of 7.5×10⁸ per tipand pelleted by centrifuging at 1000 rpm for 5 minutes at 4° C.,followed by washing again with ½ volume of PBS and recentrifugation. Thepellets were washed a third time, the suspended cells collected andwashed 2× with PBS. The cells were then suspended into 10 ml PBS. BufferC1 was equilibrated at 4° C. Qiagen protease #19155 was diluted into6.25 ml cold ddH₂0 to a final concentration of 20 mg/ml and equilibratedat 4° C. 10 ml of G2 Buffer was prepared by diluting Qiagen RNAse Astock (100 mg/ml) to a final concentration of 200 μg/ml.

Buffer C1 (10 ml, 4° C.) and ddH2O (40 ml, 4° C.) were then added to the10 ml of cell suspension, mixed by inverting and incubated on ice for 10minutes. The cell nuclei were pelleted by centrifuging in a Beckmanswinging bucket rotor at 2500 rpm at 4° C. for 15 minutes. Thesupernatant was discarded and the nuclei were suspended with a vortexinto 2 ml Buffer C1 (at 4° C.) and 6 ml ddH₂O, followed by a second 4°C. centrifugation at 2500 rpm for 15 minutes. The nuclei were thenresuspended into the residual buffer using 200 μl per tip. G2 buffer (10ml) was added to the suspended nuclei while gentle vortexing wasapplied. Upon completion of buffer addition, vigorous vortexing wasapplied for 30 seconds. Quiagen protease (200 μl, prepared as indicatedabove) was added and incubated at 50° C. for 60 minutes. The incubationand centrifugation were repeated until the lysates were clear (e.g.,incubating additional 30-60 minutes, pelleting at 3000×g for 10 min., 4°C.).

Solid Human Tumor Sample Preparation and Lysis:

Tumor samples were weighed and placed into 50 ml conical tubes and heldon ice. Processing was limited to no more than 250 mg tissue perpreparation (1 tip/preparation). The protease solution was freshlyprepared by diluting into 6.25 ml cold ddH₂O to a final concentration of20 mg/ml and stored at 4° C. G2 buffer (20 ml) was prepared by dilutingDNAse A to a final concentration of 200 mg/ml (from 100 mg/ml stock).The tumor tissue was homogenated in 19 ml G2 buffer for 60 seconds usingthe large tip of the polytron in a laminar-flow TC hood in order toavoid inhalation of aerosols, and held at room temperature. Betweensamples, the polytron was cleaned by spinning at 2×30 seconds each in 2LddH₂O, followed by G2 buffer (50 ml). If tissue was still present on thegenerator tip, the apparatus was disassembled and cleaned.

Quiagen protease (prepared as indicated above, 1.0 ml) was added,followed by vortexing and incubation at 50° C. for 3 hours. Theincubation and centrifugation were repeated until the lysates were clear(e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10min., 4° C.).

Hunan Blood Preparation and Lysis:

Blood was drawn from healthy volunteers using standard infectious agentprotocols and citrated into 10 ml samples per tip. Quiagen protease wasfreshly prepared by dilution into 6.25 ml cold ddH₂O to a finalconcentration of 20 mg/ml and stored at 4° C. G2 buffer was prepared bydiluting RNAse A to a final concentration of 200 μg/ml from 100 mg/mlstock. The blood (10 ml) was placed into a 50 ml conical tube and 10 mlC1 buffer and 30 ml ddH₂O (both previously equilibrated to 4° C.) wereadded, and the components mixed by inverting and held on ice for 10minutes. The nuclei were pelleted with a Beckman swinging bucket rotorat 2500 rpm, 4° C. for 15 minutes and the supernatant discarded. With avortex, the nuclei were suspended into 2 ml C1 buffer (4° C.) and 6 mlddH₂O (4° C.). Vortexing was repeated until the pellet was white. Thenuclei were then suspended into the residual buffer using a 200 μl tip.G2 buffer (10 ml) was added to the suspended nuclei while gentlyvortexing, followed by vigorous vortexing for 30 seconds. Quiagenprotease was added (200 μl) and incubated at 50° C. for 60 minutes. Theincubation and centrifugation were repeated until the lysates were clear(e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10min., 4° C.).

Purification of Cleared Lysates:

(1) Isolation of Genomic DNA:

Genomic DNA was equilibrated (1 sample per maxi tip preparation) with 10ml QBT buffer. QF elution buffer was equilibrated at 50° C. The sampleswere vortexed for 30 seconds, then loaded onto equilibrated tips anddrained by gravity. The tips were washed with 2×15 ml QC buffer. The DNAwas eluted into 30 ml silanized, autoclaved 30 ml Corex tubes with 15 mlQF buffer (50° C.). Isopropanol (10.5 ml) was added to each sample, thetubes covered with parafin and mixed by repeated inversion until the DNAprecipitated. Samples were pelleted by centrifugation in the SS-34 rotorat 15,000 rpm for 10 minutes at 4° C. The pellet location was marked,the supernatant discarded, and 10 ml 70% ethanol (4° C.) was added.Samples were pelleted again by centrifugation on the SS-34 rotor at10,000 rpm for 10 minutes at 4° C. The pellet location was marked andthe supernatant discarded. The tubes were then placed on their side in adrying rack and dried 10 minutes at 37° C. taking care not to over drythe samples.

After drying, the pellets were dissolved into 1.0 ml TE (pH 8.5) andplaced at 50° C. for 1-2 hours. Samples were held overnight at 4° C. asdissolution continued. The DNA solution was then transferred to 1.5 mltubes with a 26 gauge needle on a tuberculin syringe. The transfer wasrepeated 5× in order to shear the DNA. Samples were then placed at 50°C. for 1-2 hours.

(2) Quantitation of Genomic DNA and Preparation for Gene AmplificationAssay:

The DNA levels in each tube were quantified by standard A₂₆₀/A₂₈₀spectrophotometry on a 1:20 dilution (5 μl DNA+95 μl ddH₂O) using the0.1 ml quartz cuvettes in the Beckman DU640 spectrophotometer. A₂₆₀/A₂₈₀ratios were in the range of 1.8-1.9. Each DNA sample was then dilutedfurther to approximately 200 ng/ml in TE (pH 8.5). If the originalmaterial was highly concentrated (about 700 ng/μl), the material wasplaced at 50° C. for several hours until resuspended.

Fluorometric DNA quantitation was then performed on the diluted material(20-600 ng/ml) using the manufacturer's guidelines as modified below.This was accomplished by allowing a Hoeffer DyNA Quant 200 fluorometerto warm-up for about 15 minutes. The Hoechst dye working solution(#H33258, 10 μl, prepared within 12 hours of use) was diluted into 100ml 1×TNE buffer. A 2 ml cuvette was filled with the fluorometersolution, placed into the machine, and the machine was zeroed. pGEM3Zf(+) (2 μl, lot #360851026) was added to 2 ml of fluorometer solutionand calibrated at 200 units. An additional 2 μl of pGEM 3Zf(+) DNA wasthen tested and the reading confirmed at 400+/−10 units. Each sample wasthen read at least in triplicate. When 3 samples were found to be within10% of each other, their average was taken and this value was used asthe quantification value.

The fluorometricly determined concentration was then used to dilute eachsample to 10 ng/μl in ddH₂O. This was done simultaneously on alltemplate samples for a single TaqMan plate assay, and with enoughmaterial to run 500-1000 assays. The samples were tested in triplicatewith Taqman™ primers and probe both B-actin and GAPDH on a single platewith normal human DNA and no-template controls. The diluted samples wereused provided that the CT value of normal human DNA subtracted from testDNA was +/−1 Ct. The diluted, lot-qualified genomic DNA was stored in1.0 ml aliquots at −80° C. Aliquots which were subsequently to be usedin the gene amplification assay were stored at 4° C. Each 1 ml aliquotis enough for 8-9 plates or 64 tests.

Gene Amplification Assay:

The PRO1295, PRO1293, PRO1265, PRO1303, PRO1269, PRO1410, PRO1317,PRO1780, PRO1555, PRO1755, PRO1558, PRO1759 and PRO1788 compounds of theinvention were screened in the following primary tumors and theresulting ΔCt values which are ≧1.0 are reported in Table 8.

TABLE 8 ΔCt values in lung and colon primary tumors and cell line modelsPrimary or Cell Tumors PRO PRO PRO PRO PRO PRO PRO PRO PRO PRO PRO PROPRO lines 1293 1269 1410 1755 1780 1788 1303 1555 1265 1317 1295 15581759 LT1 — — — — — — — — — 1.15 — — — LT1-a — — — — — — — — — 1.49 — — —LT3 — — — — — — — — 1.04 — — — — LT4 — — — — 1.16 — — — — — — — — LT7 —— — — 1.02 — — — — — — — — LT9 — — — — — — — — — 1.26 — — — LT10 — — — —— — — — — 1.68 — — — LT12 — — — — — — — — 2.17 — — — — LT13 — — 1.12 — —— 1.42 4.20 2.24 — — — — 1.42 4.45 LT15 — 1.22 2.10 — — — 1.17 1.36 3.511.16 — — — 1.82 1.15 LT16 — 1.14 1.44 1.36 — — 1.42 3.71 3.32 — — — —1.45 3.99 LT17 — 1.26 — — — — — — 1.02 1.74 — — — LT18 — — — 1.18 — — —— — — — — — CT2 — — 2.36 2.35 — — — — — — — — — CT3 — — 1.09 — — 1.35 —— — — — — — CT8 — — — 1.64 — 1.26 — — — — — — — CT10 — — 1.41 2.05 —1.37 — — — — — — — CT12 — — — 1.15 — 1.24 — — — — — — — CT14 — — 1.461.40 — 2.58 — — — — — — — CT15 — — — — — — — 1.34 — — — — — 1.62 CT16 —— — — — — 1.13 1.04 — — — — — 1.05 CT17 — — — — — — — 1.16 — — — — — CT1— — — — — 1.09 — — — — — — — CT4 — — — — — 1.22 — — — — — — — CT5 — —2.14 — — — — — — — — — — CT9 — — — — — 1.52 — — — — — — — CT11 — — 1.29— — — — — — — — — — A549 — — — — — — 1.20 2.17 — — — — — 2.11 Calu-1 — —— — — — — 1.39 — — — — — Calu-6 — — — — — — — 1.12 — — — — — H441 — — —— — — — 2.06 — — — — — H460 — — — — — — — 1.88 — — — — — SKMES1 — — — —— — — 1.90 — — — — — SW620 — — — — — — — 2.24 — — — — — Colo320 — — — —— — — 2.21 — — — — — 2.24 HT29 — — 1.22 — — — — — — — — — — HCT116 — — —— — — — 2.46 — — — — — 2.66 LT22 — — — 1.26 1.07 — — — — 2.69 — — — HF-— — — — — — — 2.63 — — — — — 000716 2.73 HF- — — — — — — — 2.58 — — — —— 000733 2.71 1.39 HF- — — — — — — — 4.99 — — — — — 000611 HF- 2.33 — —— — — — 3.13 — — 1.49 — — 000539 2.55 HF- — — — — — — — 1.32 — — — — —000575 HF- — — — — — — — — — — 1.09 — — 000698 HF- — — — — — — — 1.59 —— 1.11 — — 000545 1.68 HF- — — — — — — — 1.37 — — 1.27 — — 000631 HF-1.71 — — — — — — 3.63 — — 1.97 1.39 1.11 000840 HF- — — — — — — — 1.99 —— — 1.24 — 000842 HF- 1.13 — — — — — — — — — — 1.01 1.32 000795 HF — — —— — — — — — — — 1.50 — 001294 HF- — — — — — — — — — — — 2.88 1.51 001296HF- — — — — — — — — — — — 1.37 — 001299PRO1265

PRO1265 (DNA60764-1533) was also reexamined along with selected tumorsfrom the above initial screen with framework mapping. Table 9 indicatesthe chromosomal mapping of the framework markers that were used in thepresent example. The framework markers are located approximately every20 megabases and were used to control aneuploidy.

PRO1265 was also reexamined with epicenter mapping. The markersindicated in Table 10 are located in close proximity (in the genome) toDNA60764-1533, and are used to assess the relative amplification in theimmediate vicinity of Chromosome 19 wherein the molecule is located. Thedistance between individual markers is measured in centirays (cR), whichis a radiation breakage unit approximately equal to a 1% chance of abreakage between two markers. One cR is very roughly equivalent to 20kilobases. The marker SHGC-33698 is closest to DNA60764-1533.

TABLE 9 Framework Markers Along Chromosome 19 Map Position on Chromosome19 Stanford Human Genome Center Marker Name S12 AFMa107xc9 S50SHGC-31335 S105 SHGC-34102 S155 SHGC-16175

TABLE 10 Epicenter Markers Along Chromosome 19 used for DNA60764-1533Map Position on Stanford Human Genome Distance to next Chromosome 19Center Marker Name Marker (cR) DNA34353 — maps to S158 DNA40620 — mapsto S160 DNA54002 — maps to S160 S160 SHGC-34723 21 DNA60764 — — S161SHGC-30929 15 S162 SHGC-10328 17 S163 AFMa115wg5 —The ΔCt values of the above described framework markers along Chromosome19 relative to PRO1265 are indicated for selected tumors in Table 11.

TABLE 11 Amplification of framework markers relative to DNA60764-1533(ΔCt) Framework Markers Tumor S12 DNA60764-1533 S50 S105 S155 LT1 0.160.06 −0.42 0.11 −1.56 LT1a 0.05 −0.27 0.17 0.40 0.00 LT2 0.48 0.41 0.520.13 −0.36 LT3 0.27 0.83 0.11 0.50 1.04 LT4 0.48 0.67 0.20 0.56 −0.35LT6 0.72 0.74 0.32 0.35 0.24 LT7 0.82 0.85 0.95 0.95 0.75 LT9 0.72 0.610.19 0.64 −0.35 LT10 0.82 0.98 0.62 0.53 0.32 LT11 0.13 0.25 0.55 −0.340.70 LT12 0.04 0.60 0.21 −0.17 2.17 LT13 −0.06 0.57 −0.30 −0.05 2.24LT15 −0.03 −0.77 0.12 −0.04 3.51 LT16 0.46 1.37 0.51 0.23 3.32 LT17 0.370.74 0.21 0.22 1.02 LT18 0.39 0.57 0.11 0.16 0.52 LT22 0.79 0.76 −0.050.16 0.59

DISCUSSION AND CONCLUSION

PRO1269 (DNA66520-1536):

The ΔCt values for DNA66520-1536 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA66520-1536 encoding PRO1269 occurred in primary lung tumors: LT15,LT16 and LT17. Because amplification of DNA66520-1536 occurs in variouslung tumors, it is highly probable to play a significant role in tumorformation or growth. As a result, antagonists (e.g., antibodies)directed against the protein encoded by DNA66520-1536 (PRO1269) would beexpected to have utility in cancer therapy.

PRO1410 (DNA68874-1622):

The ΔCt values for DNA68874-1622 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy, theabove data indicates that significant amplification of nucleic acidDNA68874-1622 encoding PRO1410 occurred: (1) in primary lung tumors:LT13, LT15 and LT16; (2) in primary colon tumors: CT2, CT3, CT5, CT10,CT11, and CT14; and (3) in colon cell line HT29. Because amplificationof DNA68874-1622 occurs in various lung and colon tumors, it is highlyprobable to play a significant role in tumor formation or growth. As aresult, antagonists (e.g., antibodies) directed against the proteinencoded by DNA68874-1622 (PRO1410) would be expected to have utility incancer therapy.

PRO1755 (DNA76396-1698):

The ΔCt values for DNA76396-1698 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA76396-1698 encoding PRO1755 occurred: (1) in primary lung tumors:LT16, LT18 and LT22; and (2) in primary colon tumors: CT2, CT8, CT10,CT12, and CT14. Because amplification of DNA76396-1698 occurs in variouslung and colon tumors, it is highly probable to play a significant rolein tumor formation or growth. As a result, antagonists (e.g.,antibodies) directed against the protein encoded by DNA76396-1698(PRO1755) would be expected to have utility in cancer therapy.

PRO1780 (DNA71169-1709):

The ΔCt values for DNA71169-1709 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA71169-1709 encoding PRO1780 occurred in primary lung tumors: LT4, LT7and LT22. Because amplification of DNA71169-1709 occurs in various lungtumors, it is highly probable to play a significant role in tumorformation or growth. As a result, antagonists (e.g., antibodies)directed against the protein encoded by DNA71169-1709 (PRO1780) would beexpected to have utility in cancer therapy.

PRO1788 (DNA77652-2505):

The ΔCt values for DNA77652-2505 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA77652-2505 encoding PRO1798 occurred in primary colon tumors: CT1,CT3, CT4, CT8, CT9, CT10, CT12, and CT14. Because amplification ofDNA77652-2505 occurs in various colon tumors, it is highly probable toplay a significant role in tumor formation or growth. As a result,antagonists (e.g., antibodies) directed against the protein encoded byDNA77652-2505 (PRO1788) would be expected to have utility in cancertherapy.

PRO1295 (DNA59218-1559):

The ΔCt values for DNA59218-1559 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA59218-1559 encoding PRO1295 occurred: (1) in primary lung tumors:HF-000631 and HF-000840; (2) colon tumor centers: HF-000539 andHF-000698; and (3) in breast tumor center HF-000545. Becauseamplification of DNA59218-1559 occurs in various tumors, it is highlyprobable to play a significant role in tumor formation or growth. As aresult, antagonists (e.g., antibodies) directed against the proteinencoded by DNA59218-1559 (PRO1295) would be expected to have utility incancer therapy.

PRO1293 (DNA60618-1557):

The ΔCt values for DNA60618-1557 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA60618-1557 encoding PRO1293 occurred: (1) in primary lung tumorHF-000840; and (2) in colon tumor centers: HF-000539 and HF-000795.Because amplification of DNA60618-1557 occurs in various lung and colontumors, it is highly probable to play a significant role in tumorformation or growth. As a result, antagonists (e.g., antibodies)directed against the protein encoded by DNA60618-1557 (PRO1293) would beexpected to have utility in cancer therapy.

PRO1303 (DNA65409-1566):

The ΔCt values for DNA65409-1566 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA65409-1566 encoding PRO1303 occurred: (1) in primary lung tumors:LT13, LT15 and LT16; (2) in lung cell line A549; and (3) in colon tumorCT16. Because amplification of DNA65409-1566 occurs in various tumors,it is highly probable to play a significant role in tumor formation orgrowth. As a result, antagonists (e.g., antibodies) directed against theprotein encoded by DNA65409-1566 (PRO1566) would be expected to haveutility in cancer therapy.

PRO1555 (DNA73744-1665):

The ΔCt values for DNA73744-1665 in a variety of tumors are reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA73744-1665 encoding PRO1555 occurred: (1) in primary lung tumors:LT13, LT15, LT16, HF-000631, HF-000840, and HF-000842; (2) in lung celllines: A549, Calu-1, Calu-6, H441, H460, and SKMES1; (3) in primarycolon tumors: CT15, CT16, CT17, and colon tumor centers HF-000539 andHF-000575; (4) in colon cell lines: SW620, Colo320 and HCT116; (5) inbreast tumor center HF-000545; (6) in kidney tumor center HF-000611; and(7) in testis tumor margin HF-000716 and testis tumor center HF-000733.Because amplification of DNA73744-1665 occurs in various tumors, it ishighly probable to play a significant role in tumor formation or growth.As a result, antagonists (e.g., antibodies) directed against the proteinencoded by DNA73744-1665 (PRO1555) would be expected to have utility incancer therapy.

PRO1265 (DNA60764-1533):

The ΔCt values for DNA60764-1533 in a variety of lung tumors arereported above. A ΔCt value of >1 was typically used as the thresholdvalue for amplification scoring, as this represents a doubling of genecopy. The above data indicates that significant amplification ofDNA60765-1533 occurred in primary lung tumors LT3, LT12, LT13, LT15,LT16 and LT17. The ΔCt values of these hits are 1.03, 2.17, 2.24, 3.51,3.32 and 1.02. This represents an increase in gene copy of approximately2.04, 4.50, 4.72, 11.39, 9.99 and 2.03.

Amplification has also been confirmed framework mapping forDNA60764-1533 in LT16. The reported ΔCt value was 1.37, which representsa 2.58 fold increase in gene copy relative to normal tissue. Epicentermapping has also confirmed amplification of DNA60764-1533 in LT12, LT13,LT15, LT16, CT1, CT4, CT5, CT7 and CT11. These tumors report ΔCt valuesof 2.35, 2.37, 3.88, 3.32 in the lung tumors and 1.74, 1.86, 3.28, 1.29and 2.32 in the colon tumors. Relative to normal tissue, this representsan increase in gene copy of approximately 5.10, 5.17, 14.72 and 9.98 inthe lung tumors and 3.34, 3.63, 9.71, 2.45 and 4.99 in the colon tumors.

In contrast, the amplification of the closest known framework markers,epicenter markers and the comparison sequences does not occur to agreater extent than that of DNA60764-1533. This strongly suggests thatDNA60764-1533 is the gene responsible for the amplification of theparticular region in Chromosome 19. Because amplification ofDNA60764-1533 occurs in various lung and colon tumors, it is highlyprobably to play a significant role in tumor formation or growth. As aresult, antagonists (e.g., antibodies) directed against the proteinencoded by DNA60764-1533 would be expected to have utility in cancertherapy.

PRO1317 (DNA71166-1685):

The ΔCt values for DNA71166-1685 in a variety of tumors arc reportedabove. A ΔCt of >1 was typically used as the threshold value foramplification scoring, as this represents a doubling of gene copy. Theabove data indicates that significant amplification of nucleic acidDNA71166-1685 encoding PRO1317 occurred in primary lung tumors LT1,LT1a, LT9, LT10, LT15, LT17 and LT22. Because amplification ofDNA71166-1685 occurs in various tumors, it is likely associated withtumor formation and/or growth. As a result, antagonists (e.g.,antibodies) directed against PRO1317 would be expected to be useful incancer therapy.

Summary

Because amplification of the various DNA's as described above occurs invarious tumors, they are likely associated with tumor formation and/orgrowth. As a result, antagonists (e.g., antibodies) directed againstthese polypeptides would be expected to be useful in cancer therapy.

Example 144 Stimulatory Activity in Mixed Lvmphocyte Reaction (MLR)Assay (Assay 24)

This example shows that certain polypeptides of the invention are activeas a stimulator of the proliferation of stimulated T-lymphocytes.Compounds which stimulate proliferation of lymphocytes are usefultherapeutically where enhancement of an immune response is beneficial. Atherapeutic agent may take the form of antagonists of the polypeptide ofthe invention, for example, murine-human chimeric, humanized or humanantibodies against the polypeptide.

The basic protocol for this assay is described in Current Protocols inImmunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclearcells (PBMC) are isolated from mammalian individuals, for example ahuman volunteer, by leukopheresis (one donor will supply stimulatorPBMCs, the other donor will supply responder PBMCs). If desired, thecells are frozen in fetal bovine serum and DMSO after isolation. Frozencells may be thawed overnight in assay media (37° C., 5% CO₂) and thenwashed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetalbovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%nonessential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

-   -   100:1 of test sample diluted to 1% or to 0.1%,    -   50:1 of irradiated stimulator cells, and    -   50:1 of responder PBMC cells.        100 microliters of cell culture media or 100 microliter of        CD4-IgG is used as the control. The wells are then incubated at        37° C., 5% CO₂ for 4 days. On day 5, each well is pulsed with        tritiated thymidine (1.0 mC/well; Amersham). After 6 hours the        cells are washed 3 times and then the uptake of the label is        evaluated.

In another variant of this assay, PBMCs are isolated from the spleens ofBalb/c mice and C57B6 mice. The cells are teased from freshly harvestedspleens in assay media (RPMI; 10% fetal bovine serum, 1%penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential aminoacids, 1% pyruvate) and the PBMCs are isolated by overlaying these cellsover Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20minutes, collecting and washing the mononuclear cell layer in assaymedia and resuspending the cells to 1×10⁷ cells/ml of assay media. Theassay is then conducted as described above.

Positive increases over control are considered positive with increasesof greater than or equal to 180% being preferred. However, any valuegreater than control indicates a stimulatory effect for the testprotein.

The following PRO polypeptides tested positive in this assay: PRO1246and PRO1343.

Example 145 Mouse Kidney Mesangial Cell Proliferation Assay (Assay 92)

This assay shows that certain polypeptides of the invention act toinduce proliferation of mammalian kidney mesangial cells and, therefore,are useful for treating kidney disorders associated with decreasedmesangial cell function such as Berger disease or other nephropathiesassociated with Sch6nlein-Henoch purpura, celiac disease, dermatitisherpetiformis or Crohn disease. The assay is performed as follows. Onday one, mouse kidney mesangial cells are plated on a 96 well plate ingrowth media (3:1 mixture of Dulbeeco's modified Eagle's medium andHam's F12 medium, 95% fetal bovine serum, 5% supplemented with 14 mMHEPES) and grown overnight. On day 2, PRO polypeptides are diluted at 2concentrations (1% and 0.1%) in serum-free medium and added to thecells. Control samples are serum-free medium alone. On day 4, 20 μl ofthe Cell Titer 96 Aqueous one solution reagent (Progema) was added toeach well and the colormetric reaction was allowed to proceed for 2hours. The absorbance (OD) is then measured at 490 nm. A positive in theassay is anything that gives an absorbance reading which is at least 15%above the control reading.

The following polypeptide tested positive in this assay: PRO1265,PRO1244 and PRO1382.

Example 146 Induction of Pancreatic β-Cell Precursor Differentiation(Assay 89)

This assay shows that certain polypeptides of the invention act toinduce differentiation of pancreatic β-cell precursor cells into maturepancreatic β-cells and, therefore, are useful for treating variousinsulin deficient states in mammals, including diabetes mellitus. Theassay is performed as follows. The assay uses a primary culture of mousefetal pancreatic cells and the primary readout is an alteration in theexpression of markers that represent either β-cell precursors or matureβ-cells. Marker expression is measured by real time quantitative PCR(RTQ-PCR); wherein the marker being evaluated is insulin.

The pancreata are dissected from E14 embryos (CD1 mice). The pancreataare then digested with collagenase/dispase in F12/DMEM at 37° C. for 40to 60 minutes (collagenase/dispase, 1.37 mg/ml, Boehringer Mannheim,#1097113). The digestion is then neutralized with an equal volume of 5%BSA and the cells are washed once with RPM11640. At day 1, the cells areseeded into 12-well (issue culture plates (pre-coated with laminin, 20μg/ml in PBS, Boehringer Mannheim, #124317). Cells from pancreata from1-2 embryos are distributed per well. The culture medium for thisprimary culture is 14F/1640. At day 2, the media is removed and theattached cells washed with RPMI/1640. Two mls of minimal media are addedin addition to the protein to be tested. At day 4, the media is removedand RNA prepared from the cells and marker expression analyzed by realtime quantitative RT-PCR. A protein is considered to be active in theassay if it increases the expression of the relevant β-cell marker ascompared to untreated controls.

14F/1640 is RPM11640 (Gibco) plus the following:

-   -   group A 1:1000    -   group B 1:1000    -   recombinant human insulin 10 μg/ml    -   Aprotinin (50 μg/ml) 1:2000 (Boehringer manheim #981532)    -   Bovine pituitary extract (BPE) 60 μg/ml    -   Gentamycin 100 ng/ml        Group A: (in 10 ml PBS)    -   Transferrin, 100 mg (Sigma T2252)    -   Epidermal Growth Factor, 100 μg (BRL 100004)    -   Triiodothyronine, 10 μl of 5×10⁻⁶ M (Sigma T5516)    -   Ethanolamine, 10 μl of 10⁻¹ M (Sigma E0135)    -   Phosphoethalamine, 100 μl of 10⁻¹ M (Sigma P0503)    -   Selenium, 4 μl of 10⁻¹ M (Aesar #12574)        Group C: (in 10 ml 100% ethanol)    -   Hydrocortisone, 2 μl of 5×10⁻³ M (Sigma #H0135)    -   Progesterone, 100 μl of 1×10⁻³ M (Sigma #P6149)    -   Forskolin, 500 μl of 20 mM (Calbiochem #344270)        Minimal Media:

RPMI 1640 plus transferrin (10 μg/ml), insulin (1 μg/ml), gentamycin(100 ng/ml), aprotinin (50 μg/ml) and BPE (15 μg/ml).

Defined Media:

RPMI 1640 plus transferrin (10 μg/ml), insulin (1 μg/ml), gentamycin(100 ng/ml) and aprotinin (50 μg/ml).

The following polypeptides were positive in this assay: PRO1275 andPRO1474.

Example 147 Fetal Hemoglobin Induction in an Erythroblastic Cell Line(Assay 107)

This assay is useful for screening PRO polypeptides for the ability toinduce the switch from adult hemoglobin to fetal hemoglobin in anerythroblastic cell line. Molecules testing positive in this assay areexpected to be useful for therapeutically treating various mammalianhemoglobin-associated disorders such as the various thalassemias. Theassay is performed as follows. Erythroblastic cells are plated instandard growth medium at 1000 cells/well in a 96 well format. PROpolypeptides are added to the growth medium at a concentration of 0.2%or 2% and the cells are incubated for 5 days at 37° C. As a positivecontrol, cells are treated with 100 μM hemin and as a negative control,the cells are untreated. After 5 days, cell lysates are prepared andanalyzed for the expression of gamma globin (a fetal marker). A positivein the assay is a gamma globin level at least 2-fold above the negativecontrol.

The following polypeptides tested positive in this assay: PRO1478,PRO1265, PRO1412, PRO1279, PRO1304, PRO1306, PRO1418, PRO1410 andPRO1575.

Example 148 Detection of Polypeptides that Affect Glucose and/or FFAUptake in Skeletal Muscle (Assay 106)

This assay is designed to determine whether PRO polypeptides show theability to affect glucose or FFA uptake by skeletal muscle cells. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by skeletal muscle would bebeneficial including, for example, diabetes or hyper- orhypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primaryrat differentiated skeletal muscle, and allowed to incubate overnight.Then fresh media with the PRO polypeptide and +/−insulin are added tothe wells. The sample media is then monitored to determine glucose andFFA uptake by the skeletal muscle cells. The insulin will stimulateglucose and FFA uptake by the skeletal muscle, and insulin in mediawithout the PRO polypeptide is used as a positive control, and a limitfor scoring. As the PRO polypeptide being tested may either stimulate orinhibit glucose and FFA uptake, results are scored as positive in theassay if greater than 1.5 times or less than 0.5 times the insulincontrol.

The following PRO polypeptides tested positive as either stimulators orinhibitors of glucose and/or FFA uptake in this assay: PRO1130, PRO1275,PRO1418, PRO1555 and PRO1787.

Example 149 Detection of PRO Polypeptides that Affect Glucose or FFAUptake by Primary Rat Adipocytes (Assay 94)

This assay is designed to determine whether PRO polypeptides show theability to affect glucose or FFA uptake by adipocyte cells. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by adipocytes would bebeneficial including, for example, obesity, diabetes or hyper- orhypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primaryrat adipocytes, and allowed to incubate overnight. Samples are taken at4 and 16 hours and assayed for glycerol, glucose and FFA uptake. Afterthe 16 hour incubation, insulin is added to the media and allowed toincubate for 4 hours. At this time, a sample is taken and glycerol,glucose and FFA uptake is measured. Media containing insulin without thePRO polypeptide is used as a positive reference control. As the PROpolypeptide being tested may either stimulate or inhibit glucose and FFAuptake, results are scored as positive in the assay if greater than 1.5times or less than 0.5 times the insulin control.

The following PRO polypeptides tested positive as stimulators of glucoseand/or FFA uptake in this assay: PRO1265, PRO1283, PRO1279, PRO1303,PRO1306, PRO1325, PRO1565 and PRO1567.

The following PRO polypeptides tested positive as inhibitors of glucoseand/or FFA uptake in this assay: PRO1194, PRO1190, PRO1326, PRO1343,PRO1480, PRO1474, PRO1575 and PRO1760.

Example 150 Chondrocyte Re-differentiation Assay (Assay 110)

This assay shows that certain polypeptides of the invention act toinduce redifferentiation of chondrocytes, therefore, are expected to beuseful for the treatment of various bone and/or cartilage disorders suchas, for example, sports injuries and arthritis. The assay is performedas follows. Porcine chondrocytes are isolated by overnight collagenasedigestion of articulary cartilage of metacarpophalangeal joints of 4-6month old female pigs. The isolated cells are then seeded at 25,000cells/cm² in Ham F-12 containing 10% FBS and 4 μg/ml gentamycin. Theculture media is changed every third day and the cells are then seededin 96 well plates at 5,000 cells/well in 100 μl of the same mediawithout serum and 100 μl of the test PRO polypeptide, 5 nM staurosporin(positive control) or medium alone (negative control) is added to give afinal volume of 200 μl/well. After 5 days of incubation at 37° C., apicture of each well is taken and the differentiation state of thechondrocytes is determined. A positive result in the assay occurs whenthe redifferentiation of the chondrocytes is determined to be moresimilar to the positive control than the negative control.

The following polypeptide tested positive in this assay: PRO1265,PRO1250. PRO1430, PRO1356, PRO1275, PRO1274, PRO1286, PRO1273, PRO1283,PRO1279, PRO1306, PRO1325, PRO1343, PRO1418, PRO1565, PRO1474, PRO1787,PRO1556 and PRO1801.

Example 151 Induction of Pancreatic β-Cell Precursor Proliferation(Assay 117)

This assay shows that certain polypeptides of the invention act toinduce an increase in the number of pancreatic β-cell precursor cellsand, therefore, are useful for treating various insulin deficient statesin mammals, including diabetes mellitus. The assay is performed asfollows. The assay uses a primary culture of mouse fetal pancreaticcells and the primary readout is an alteration in the expression ofmarkers that represent either β-cell precursors or mature β-cells.Marker expression is measured by real time quantitative PCR (RTQ-PCR);wherein the marker being evaluated is a transcription factor calledPd×1.

The pancreata are dissected from E14 embryos (CD1 mice). The pancreataare then digested with collagenase/dispase in F12/DMEM at 37° C. for 40to 60 minutes (collagenase/dispase, 1.37 mg/ml, Boehringer Mannheim,#1097113). The digestion is then neutralized with an equal volume of 5%BSA and the cells are washed once with RPMI1640. At day 1, the cells areseeded into 12-well tissue culture plates (pre-coated with laminin, 20μg/ml in PBS, Boehringer Mannheim, #124317). Cells from pancreata from1-2 embryos are distributed per well. The culture medium for thisprimary culture is 14F/1640. At day 2, the media is removed and theattached cells washed with RPMI/1640. Two mls of minimal media arc addedin addition to the protein to be tested. At day 4, the media is removedand RNA prepared from the cells and marker expression analyzed by realtime quantitative RT-PCR. A protein is considered to be active in theassay if it increases the expression of the relevant β-cell marker ascompared to untreated controls.

14F/1640 is RPMI1640 (Gibco) plus the following:

-   -   group A 1:1000    -   group B 1:1000    -   recombinant human insulin 10 μg/ml    -   Aprotinin (50 μg/ml) 1:2000 (Boehringer manheim #981532)    -   Bovine pituitary extract (BPE) 60 μg/ml    -   Gentamycin 100 ng/ml        Group A: (in 10ml PBS)    -   Transferrin, 100 mg (Sigma T2252)    -   Epidermal Growth Factor, 100 μg (BRL 100004)    -   Triiodothyronine, 100 μl of 5×10⁻⁶ M (Sigma T5516)    -   Ethanolamine, 100 μl of 10⁻¹ M (Sigma E0135)    -   Phosphoethalamine, 100 μl of 10⁻¹ M (Sigma P0503)    -   Selenium, 4 μl of 10⁻¹ M (Aesar #12574)        Group C: (in 10 ml 100% ethanol)    -   Hydrocortisone, 2 μl of 5×10⁻³ M (Sigma #H0135)    -   Progesterone, 100 μl of 1×10⁻³ M (Sigma #P6149)    -   Forskolin, 500 μl of 20 mM (Calbiochem #344270)        Minimal Media:

RPMI1640 plus transferrin (10 μg/ml), insulin (1 μg/ml), gentamycin (100ng/ml), aprotinin (50 μg/ml) and BPE (15 μg/ml).

Defined Media:

RPMI 1640 plus transferrin (10 μg/ml), insulin (1 μg/ml), gentamycin(100 ng/ml) and aprotinin (50 μg/ml).

The following polypeptides tested positive in this assay: PRO1382 andPRO1561.

Example 152 Proliferation of Rat Utricular Supporting Cells (Assay 54)

This assay shows that certain polypeptides of the invention act aspotent mitogens for inner ear supporting cells which are auditory haircell progenitors and, therefore, are useful for inducing theregeneration of auditory hair cells and treating hearing loss inmammals. The assay is performed as follows. Rat UEC-4 utricularepithelial cells are aliquoted into 96 well plates with a density of3000 cells/well in 200 μl of serum-containing medium at 33° C. The cellsare cultured overnight and are then switched to serum-free medium at 37°C. Various dilutions of PRO polypeptides (or nothing for a control) arethen added to the cultures and the cells are incubated for 24 hours.After the 24 hour incubation, ³H-thyrmidine (1 μCi/well) is added andthe cells are then cultured for an additional 24 hours. The cultures arcthen washed to remove unincorporated radiolabel, the cells harvested andCpm per well determined. Cpm of at least 30% or greater in the PROpolypeptide treated cultures as compared to the control cultures isconsidered a positive in the assay.

The following polypeptides tested positive in this assay: PRO1340.

Example 153 Chondrocyte Proliferation Assay (Assay 111)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to induce the proliferation and/orredifferentiation of chondrocytes in culture. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of various bone and/or cartilage disorders suchas, for example, sports injuries and arthritis.

Porcine chondrocytes are isolated by overnight collagenase digestion ofarticular cartilage of the metacarpophalangeal joint of 4-6 month oldfemale pigs. The isolated cells are then seeded at 25,000 cells/cm² inHam F-12 containing 10% FBS and 4 μg/ml gentamycin. The culture media ischanged every third day and the cells are reseeded to 25,000 cells/cm²every five days. On day 12, the cells are seeded in 96 well plates at5,000 cells/well in 100 μl of the same media without serum and 100 μl ofeither serum-free medium (negative control), staurosporin (finalconcentration of 5 nM; positive control) or the test PRO polypeptide areadded to give a final volume of 200 μl/well. After 5 days at 37° C., 20μl of Alamar blue is added to each well and the plates are incubated foran additional 3 hours at 37° C. The fluorescence is then measured ineachwell (Ex:530 nm; Em: 590 nm). The fluorescence of a plate containing 200μl of the serum-free medium is measured to obtain the background. Apositive result in the assay is obtained when the fluorescence of thePRO polypeptide treated sample is more like that of the positive controlthan the negative control.

The following PRO polypeptides tested positive in this assay: PRO1265,PRO1412, PRO1347, PRO1279, PRO1410 and PRO1474.

Example 154 Inhibition of Heart Neonatal Hypertrophy Induced by LIF+ET−1(Assay 74)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to inhibit neonatal heart hypertrophyinduced by LIF and endothelin-1 (ET-1). A test compound that provides apositive response in the present assay would be useful for thetherapeutic treatment of cardiac insufficiency diseases or disorderscharacterized or associated with an undesired hypertrophy of the cardiacmuscle.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats (180 μl at7.5×10⁴/ml, serum <0.1, freshly isolated) are introduced on day 1 to96-well plates previously coated with DMEM/F12+4% FCS. Test PROpolypeptide samples or growth medium alone (negative control) are thenadded directly to the wells on day 2 in 20 μl volume. LIF+ET−1 are thenadded to the wells on day 3. The cells are stained after an additional 2days in culture and are then scored visually the next day. A positive inthe assay occurs when the PRO polypeptide treated myocytes are visuallysmaller on the average or less numerous than the untreated myocytes.

The following PRO polypeptides tested positive in this assay: PRO1760.

Example 155 Tissue Expression Distribution

Oligonucleotide probes were constructed from some of the PROpolypeptide-encoding nucleotide sequences shown in the accompanyingfigures for use in quantitative PCR amplification reactions. Theoligonucleotide probes were chosen so as to give an approximately200-600 base pair amplified fragment from the 3′ end of its associatedtemplate in a standard PCR reaction. The oligonucleotide probes wereemployed in standard quantitative PCR amplification reactions with cDNAlibraries isolated from different human adult and/or fetal tissuesources and analyzed by agarose gel electrophoresis so as to obtain aquantitative determination of the level of expression of the PROpolypeptide-encoding nucleic acid in the various tissues tested.Knowledge of the expression pattern or the differential expression ofthe PRO polypeptide-encoding nucleic acid in various different humantissue types provides a diagnostic marker useful for tissue typing, withor without other tissue-specific markers, for determining the primarytissue source of a metastatic tumor, and the like. These assays providedthe following results.

DNA Molecule Tissues With Significant Expression Tissues LackingSignificant Expression DNA19902-1669 HUVEC cells, colon tumor dendriticcells, lymphoblast cells, heart DNA23322-1393 uterus, colon tumor,prostate cartilage DNA26846-1397 lymphoblast cells uterus, heart,cartilage DNA56107-1415 spleen, substantia nigra, colon tumor cartilageDNA56406-1704 THP-1 macrophages, uterus, spleen endothelial cells,prostate, cartilage DNA56529-1647 liver, kidney, brain adenocarcionoma,lung, bone marrow DNA56862-1343 endothelial cells, substantia nigracolon tumor, lymphoblast cells, uterus hippocampus DNA57254-1477 kidneylung, placenta, brain DNA58730-1607 bone marrow, kidney lung, brainDNA58732-1650 lung, bone marrow brain, liver DNA58828-1519adenocarcinoma lung, retina, small intestine DNA58852-1637 uterus colontumor, heart, brain DNA59212-1627 uterus prostate, cartilage, heartDNA59219-1613 spleen, dendrocytes, prostate, uterus substantia nigra,colon tumor, heart DNA59817-1703 bone marrow lung, small intestine,placenta DNA60278-1530 prostate, colon tumor uterus, cartilageDNA60608-1577 kidney, bone marrow breast carcinoma, small intestine,lung DNA60611-1524 breast carcinoma lung, small intestine, retinaDNA60740-1615 breast carcinoma, adenocarcinoma lung, small intestine,brain DNA62809-1531 THP-1 macrophages uterus, spleen, brain, colon tumorDNA62815-1576 colon tumor, uterus, prostate spleen, brain, heart,cartilage DNA62845-1684 liver, bone marrow adenocarcinoma, lung, brainDNA64849-1604 kidney lung, pancreas, liver, thyroid DNA64863-1573 lung,brain, kidney, bone marrow liver, pancreas DNA64881-1602 uterus heart,spleen, brain, endothelial cells DNA64902-1667 urerus prostate, brain,heart, spleen DNA64952-1568 lung, brain pancreas DNA65403-1565 spleen,dendrocytes, THP-1 macrophages endothelial cells, colon tumor,lymphoblasts DNA65408-1578 prostate, spleen, dendrocytes uterus, heart,substantia nigra DNA65423-1595 testis breast carcinoma, retina, smallintestine DNA66512-1564 heart, uterus, prostate, cartilage endothelialcells DNA66519-1535 dendrocytes, lymphoblasts, uterus substantia nigra,prostate, spleen DNA66521-1583 uterus, heart, hippocampus cartilage,dendrocytes, spleen DNA66658-1584 prostate, uterus, hippocampus, spleencolon tumor, cartilage, heart DNA66672-1586 spleen heart, prostate,brain, uterus DNA66674-1599 uterus, prostate heart, brain, spleen,cartilage, colon tumor DNA68836-1656 kidney lung, brain, bone marrow,liver DNA68871-1638 uterus, colon tumor, prostate heart, cartilage,brain, spleen DNA68880-1676 heart, endothelial cells, brain, uterusTHP-1 macrophages DNA68885-1678 uterus, colon tumor, prostate brain,heart, cartilage, endothelial cells DNA71180-1655 brain lung, bonemarrow, liver, kidney DNA71184-1634 breast carcinoma, bone marrow,testis brain, adrenal gland DNA71234-1651 kidney, bone marrow lung,brain, placenta DNA71277-1636 prostate, cartilage, heart, uterus colontumor, substantia nigra, endothelial cells DNA71286-1687 uterus,prostate, brain, cartilage heart DNA71883-1660 aortic endothelial cellslung, retina, small intestine, kidney DNA73492-1671 breast carcinoma,aortic endothelial cells lung, brain, testis bone marrow DNA73734-1680prostate, spleen heart, cartilage, brain, uterus DNA73735-1681 prostatebrain, heart, cartilage, spleen DNA73736-1657 spleen, substantia nigra,hippocampus, prostate, heart, uterus, dendrocytes cartilageDNA73737-1658 uterus prostate, heart, spleen, cartilage DNA73742-1662spleen, uterus, prostate dendrocytes, colon tumor, endothelial cellsDNA73746-1654 prostate uterus, heart, brain, cartilage, spleenDNA73760-1672 breast carcinoma retina, brain, kidney, liver, testisDNA76393-1664 endothelial cells, cartilage, uterus brain, prostateDNA76398-1699 hippocampus, prostate, THP-1 heart, uterus, spleen,dendrocytes macrtophages DNA76399-1700 IM-9 lymphoblasts prostate,spleen, heart, cartilage, uterus DNA76522-2500 colon tumor uterus,prostate, brain, heart, cartilage DNA77301-1708 brain lung, smallintestine, kidney, liver DNA77648-1688 retina, breast carcinoma, kidney,liver, brain, lung bone marrow DNA77568-1626 brain lung, liver,placenta, heart DNA58727-1474 HUVEC, dendrocytes, uterus substantianigra, hippocampus, prostate, colon tumor DNA61185-1646 colon tumor,HUVEC uterus, dendrocytes, substantia nigra DNA61608-1606 colon tumor,dendrocytes, spleen, testis substantia nigra, placenta DNA66304-1546prostate, testis uterus, brain, heart, colon tumor, adrenal glandDNA71213-1659 brain, spleen, HUVEC, colon tumor prostate, uterus, heart,cartilage DNA62812-1594 heart placenta, testis, uterus, adrenal gland,bone marrow, prostate DNA66660-1585 colon tumor, HUVEC, testis,placenta, bone marrow uterus DNA66669-1597 heart, placenta, adrenalgland, uterus cartilage, testis, colon tumor, HUVEC, bone marrow,prostate, spleen DNA68866-1644 testis, colon tumor, prostate, spleen,cartilage, adrenal gland, HUVEC, placenta DNA73730-1679 testis, adrenalgland, uterus, prostate, cartilage, colon tumor, heart, placenta, uterusspleen

DEPOSIT OF MATERIAL

The following materials have been deposited with the American TypeCulture Collection, 10801 University Blvd., Manassas, Va. 20110-2209,USA (ATCC):

TABLE 12 Material ATCC Dep. No. Deposit Date DNA19902-1669 203454 Nov.3, 1998 DNA26846-1397 203406 Oct. 27, 1998 DNA56107-1415 203405 Oct. 27,1998 DNA56406-1704 203478 Nov. 17, 1998 DNA56529-1647 203293 Sep. 29,1998 DNA56531-1648 203286 Sep. 29, 1998 DNA56862-1343 203174 Sep. 1,1998 DNA57254-1477 203289 Sep. 29, 1998 DNA57841-1522 203458 Nov. 3,1998 DNA58727-1474 203171 Sep. 1, 1998 DNA58730-1607 203221 Sep. 15,1998 DNA58732-1650 203290 Sep. 29, 1998 DNA58828-1519 203172 Sep. 1,1998 DNA58852-1637 203271 Sep. 22, 1998 DNA59212-1627 203245 Sep. 9,1998 DNA59218-1559 203287 Sep. 29, 1998 DNA59219-1613 203220 Sep. 15,1998 DNA59586-1520 203288 Sep. 29, 1998 DNA59817-1703 203470 Nov. 17,1998 DNA60278-1530 203170 Sep. 1, 1998 DNA60608-1577 203126 Aug. 18,1998 DNA60611-1524 203175 Sep. 1, 1998 DNA60618-1557 203292 Sep. 29,1998 DNA60740-1615 203456 Nov. 3, 1998 DNA60764-1533 203452 Nov. 10,1998 DNA60775-1532 203173 Sep. 1, 1998 DNA61185-1646 203464 Nov. 17,1998 DNA61608-1606 203239 Sep. 9, 1998 DNA62808-1326 203358 Oct. 20,1998 DNA62809-1531 203237 Sep. 9, 1998 DNA62815-1578 203247 Sep. 9, 1998DNA62845-1684 203361 Oct. 20, 1998 DNA64842-1632 203278 Sep. 22, 1998DNA64849-1604 203468 Nov. 17, 1998 DNA64863-1573 203251 Sep. 9, 1998DNA64881-1602 203240 Sep. 9, 1998 DNA64883-1526 203253 Sep. 9, 1998DNA64885-1529 203457 Nov. 3, 1998 DNA64886-1601 203241 Sep. 9, 1998DNA64888-1542 203249 Sep. 9, 1998 DNA64889-1541 203250 Sep. 9, 1998DNA64897-1628 203216 Sep. 15, 1998 DNA64902-1667 203317 Oct. 6, 1998DNA64903-1553 203223 Sep. 15, 1998 DNA64905-1558 203233 Sep. 15, 1998DNA64950-1590 203224 Sep. 15, 1998 DNA64952-1568 203222 Sep. 15, 1998DNA65402-1540 203252 Sep. 9, 1998 DNA65403-1565 203230 Sep. 15, 1998DNA65404-1551 203244 Sep. 9, 1998 DNA65405-1547 203476 Nov. 17, 1998DNA65406-1567 203219 Sep. 15, 1998 DNA65408-1578 203217 Sep. 15, 1998DNA65409-1566 203232 Sep. 15, 1998 DNA65410-1569 203231 Sep. 15, 1998DNA65423-1595 203227 Sep. 15, 1998 DNA66304-1546 203321 Oct. 6, 1998DNA66511-1411 203228 Sep. 15, 1998 DNA66512-1564 203218 Sep. 15, 1998DNA66519-1535 203236 Sep. 15, 1998 DNA66520-1536 203226 Sep. 15, 1998DNA66521-1583 203225 Sep. 15, 1998 DNA66526-1616 203246 Sep. 9, 1998DNA66658-1584 203229 Sep. 15, 1998 DNA66659-1593 203269 Sep. 22, 1998DNA66663-1598 203268 Sep. 22, 1998 DNA66669-1597 203272 Sep. 22, 1998DNA66672-1586 203265 Sep. 22, 1998 DNA66674-1599 203281 Sep. 22, 1998DNA66675-1587 203282 Sep. 22, 1998 DNA67962-1649 203291 Sep. 29, 1998DNA68836-1656 203455 Nov. 3, 1998 DNA68864-1629 203276 Sep. 22, 1998DNA68866-1644 203283 Sep. 22, 1998 DNA68871-1638 203280 Sep. 22, 1998DNA68874-1622 203277 Sep. 22, 1998 DNA68880-1676 203319 Oct. 6, 1998DNA68885-1570 203311 Oct. 6, 1998 DNA71166-1685 203355 Oct. 20, 1998DNA71169-1709 203467 Nov. 17, 1998 DNA71180-1655 203403 Oct. 27, 1998DNA71184-1634 203266 Sep. 22, 1998 DNA71213-1659 203401 Oct. 27, 1998DNA71234-1651 203402 Oct. 27, 1998 DNA71277-1636 203285 Sep. 22, 1998DNA71282-1668 203312 Oct. 6, 1998 DNA71286-1604 203357 Oct. 20, 1998DNA71883-1660 203475 Nov. 17, 1998 DNA73401-1633 203273 Sep. 22, 1998DNA73492-1671 203324 Oct. 6, 1998 DNA73727-1673 203459 Nov. 3, 1998DNA73730-1679 203320 Oct. 6, 1998 DNA73734-1680 203363 Oct. 20, 1998DNA73735-1681 203356 Oct. 20, 1998 DNA73736-1657 203466 Nov. 17, 1998DNA73737-1658 203412 Oct. 27, 1998 DNA73739-1645 203270 Sep. 22, 1998DNA73742-1662 203316 Oct. 6, 1998 DNA73744-1665 203322 Oct. 6, 1998DNA73746-1654 203411 Oct. 27, 1998 DNA73760-1672 203314 Oct. 6, 1998DNA76396-1698 203471 Nov. 17, 1998 DNA76398-1699 203474 Nov. 17, 1998DNA76399-1700 203472 Nov. 17, 1998 DNA76401-1683 203360 Oct. 20, 1998DNA76510-2504 203477 Nov. 17, 1998 DNA76522-2500 203469 Nov. 17, 1998DNA76529-1666 203315 Oct. 6, 1998 DNA76531-1701 203465 Nov. 17, 1998DNA76532-1702 203473 Nov. 17, 1998 DNA76538-1670 203313 Oct. 6, 1998DNA76541-1675 203409 Oct. 27, 1998 DNA77301-1708 203407 Oct. 27, 1998DNA77303-2502 203479 Nov. 17, 1998 DNA77648-1688 203408 Oct. 27, 1998DNA77652-2505 203480 Nov. 17, 1998 DNA83500-2506 203391 Oct. 29, 1998DNA77568-1626 203134 Aug. 18, 1998 DNA23322-1393 203400 Oct. 27, 1998DNA59814-1486 203359 Oct. 20, 1998 DNA62812-1594 203248 Sep. 9, 1998DNA66660-1585 203279 Sep. 22, 1998 DNA76393-1664 203323 Oct. 6, 1998

These deposit were made under the provisions of the Budapest Treaty onthe International Recognition of the Deposit of Microorganisms for thePurpose of Patent Procedure and the Regulations there under (BudapestTreaty). This assures maintenance of a viable culture of the deposit for30 years from the date of deposit and for at least five (5) years afterthe most recent request for the furnishing of a sample of the depositreceived by the depository. The deposits will be made available by ATCCunder the terms of the Budapest Treaty, and subject to an agreementbetween Genentech, Inc. and ATCC, which assures that all restrictionsimposed by the depositor on the availability to the public of thedeposited material will be irrevocably removed upon the granting of thepertinent U.S. patent, assures permanent and unrestricted availabilityof the progeny of the culture of the deposit to the public upon issuanceof the pertinent U.S. patent or upon laying open to the public of anyU.S. or foreign patent application, whichever comes first, and assuresavailability of the progeny to one determined by the U.S. Commissionerof Patents and Trademarks to be entitled thereto according to 35 USC §122 and the Commissioner's rules pursuant thereto (including 37 CFR §1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if a culture ofthe materials on deposit should die or be lost or destroyed whencultivated under suitable conditions, the materials will be promptlyreplaced on notification with another of the same. Availability of thedeposited material is not to be construed as a license to practice theinvention in contravention of the rights granted under the authority ofany government in accordance with its patent laws.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by the construct deposited,since the deposited embodiment is intended as a single illustration ofcertain aspects of the invention and any constructs that arcfunctionally equivalent are within the scope of this invention. Thedeposit of material herein does not constitute an admission that thewritten description herein contained is inadequate to enable thepractice of any aspect of the invention, including the best modethereof, nor is it to be construed as limiting the scope of the claimsto the specific illustrations that it represents. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art from theforegoing description and fall within the scope of the appended claims.

1. An isolated polypeptide having at least 80% amino acid sequenceidentity to: (a) the amino acid sequence of the polypeptide of SEQ IDNO:229; (b) the amino acid sequence of the polypeptide of SEQ ID NO:229,lacking its associated signal peptide; or (c) the amino acid sequence ofthe polypeptide encoded by the full-length coding sequence of the cDNAdeposited under ATCC accession number 203268; wherein the polypeptidepromotes proliferation of inner ear supporting cells.
 2. The isolatedpolypeptide of claim 1 having at least 85% amino acid sequence identityto: (a) the amino acid sequence of the polypeptide of SEQ ID NO:229; (b)the amino acid sequence of the polypeptide of SEQ ID NO:229, lacking itsassociated signal peptide; or (c) the amino acid sequence of thepolypeptide encoded by the full-length coding sequence of the cDNAdeposited under ATCC accession number 203268; wherein the polypeptidepromotes proliferation of inner ear supporting cells.
 3. The isolatedpolypeptide of claim 1 having at least 90% amino acid sequence identityto: (a) the amino acid sequence of the polypeptide of SEQ ID NO:229; (b)the amino acid sequence of the polypeptide of SEQ ID NO:229, lacking itsassociated signal peptide; or (c) the amino acid sequence of thepolypeptide encoded by the full-length coding sequence of the cDNAdeposited under ATCC accession number 263268; wherein the polypeptidepromotes proliferation of inner ear supporting cells.
 4. The isolatedpolypeptide of claim 1 having at least 95% amino acid sequence identityto: (a) the amino acid sequence of the polypeptide of SEQ ID NO:229; (b)the amino acid sequence of the polypeptide of SEQ ID NO:229, lacking itsassociated signal peptide; or (c) the amino acid sequence of thepolypeptide encoded by the full-length coding sequence of the cDNAdeposited under ATCC accession number 203268; wherein the polypeptidepromotes proliferation of inner ear supporting cells.
 5. The isolatedpolypeptide of claim 1 having at least 99% amino acid sequence identityto: (a) the amino acid sequence of the polypeptide of SEQ ID NO:229; (b)the amino acid sequence of the polypeptide of SEQ ID NO:229, lacking itsassociated signal peptide; or (c) the amino acid sequence of thepolypeptide encoded by the full-length coding sequence of the cDNAdeposited under ATCC accession number 203268; wherein the polypeptidepromotes proliferation of inner ear supporting cells.
 6. An isolatedpolypeptide comprising: (a) the amino acid sequence of the polypeptideof SEQ ID NO:229; (b) the amino acid sequence of the polypeptide of SEQID NO:229, lacking its associated signal peptide; or (c) the amino acidsequence of the polypeptide encoded by the full-length coding sequenceof the cDNA deposited under ATCC accession number
 203268. 7. Theisolated polypeptide of claim 6 comprising the amino acid sequence ofthe polypeptide of SEQ ID NO:229.
 8. The isolated polypeptide of claim 6comprising the amino acid sequence of the polypeptide of SEQ ID NO:229,lacking its associated signal peptide.
 9. The isolated polypeptide ofclaim 6 comprising the amino acid sequence of the extracellular domainof the polypeptide of SEQ ID NO:229.
 10. The isolated polypeptide ofclaim 6 comprising the amino acid sequence of the polypeptide encoded bythe full-length coding sequence of the cDNA deposited under ATCCaccession number
 203268. 11. A chimeric polypeptide comprising apolypeptide according to claim 1 fused to a heterologous polypeptide.12. The chimeric polypeptide of claim 11, wherein said heterologouspolypeptide is an epitope tag or an Fc region of an immunoglobulin.